Implantable depots for the controlled release of therapeutic agents

ABSTRACT

The present technology relates to depots for the treatment of postoperative pain via sustained, controlled release of a therapeutic agent. In some embodiments, the depot may comprise a therapeutic region comprising an analgesic, and a control region comprising a bioresorbable polymer and a releasing agent mixed with the polymer. The releasing agent may be configured to dissolve when the depot is placed in vivo to form diffusion openings in the control region. The depot may be configured to be implanted at a treatment site in vivo and, while implanted, release the therapeutic agent at the treatment site for no less than 3 days.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to U.S.Application No. 62/569,349, filed Oct. 6, 2017, U.S. Application No.62/670,721, filed May 12, 2018, U.S. Application No. 62/640,571, filedMar. 8, 2018, and U.S. Application No. 62/723,478, filed Aug. 28, 2018,each of which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

The present technology relates to implants for controlled, sustainedrelease of therapeutic agents in vivo.

BACKGROUND OF THE INVENTION

Implantable systems for the controlled release of therapeutic agentsoffer advantages over other drug delivery methods, such as oral orparenteral methods. Devices comprised of biocompatible and/orbiodegradable polymers and therapeutic agents can be implanted inclinically desirable anatomic locations, thereby providing localizeddelivery of select agents. This localized delivery enables a substantialproportion of the agent to reach the intended target and undesirablesystemic side effects can be avoided. However, these systems oftensuffer from a lack of a true controlled release mechanism in that theytypically provide a burst of drug upon contact with surroundingphysiologic fluids followed by a residual release of drug.

In order to improve drug release in certain polymer carriers,hydrophilic polymers, such as polysorbate, have been added to thesecarriers as wetting agents to accelerate or to enhance drug release frombiocompatible polymers such polyethylene glycol (PEG) in oralformulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3):435-441). However, these formulations are intended to provide animmediate release of a hydrophobic drug into a hydrophilic environment(the in vivo physiologic fluid), where a substantial portion of theentire drug payload is immediately or aggressively released, not avariable or sustained control release.

While these drug release kinetics may be desirable in some clinicalapplications, a controlled, sustained release of a therapeutic agent canbe of clinical benefit in certain circumstances. In particular, it maybe desirable to implant a biodegradable carrier holding a large dose ofa therapeutic agent for a controlled, sustained release over time. Thismay have particular value when the carrier loaded with therapeutic agentis implanted in conjunction with an interventional or surgical procedureand, optionally, alongside or as part of an implantable medical device.

Xaracoll® (Innocoll Technologies, Athlone, Ireland) is an example of asustained-release system for postoperative pain therapy. Xaracoll® is animplantable collagen sponge loaded with bupivacaine for extended releaseto achieve a local pain block in the surgical field. As shown in FIG. 1,the bupivacaine HCl concentration in plasma peaked within 15 hours ofimplantation, thereby illustrating a duration of effect that isinadequate.

Thus, a need exists for biocompatible implantable systems capable ofproviding a highly controlled release of drug.

SUMMARY

The present technology relates to implants for controlled release of atherapeutic agent to treat a medical condition and associated systemsand methods. In particular, the present technology relates to implantsfor local, sustained release of a therapeutic agent at a surgical orinterventional site and associated systems and methods.

The subject technology is illustrated, for example, according to variousaspects described below, including with reference to FIGS. 1-32. Variousexamples of aspects of the subject technology are described as numberedclauses (1, 2, 3, etc.) for convenience. These are provided as examplesand do not limit the subject technology.

1. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 7 days.

2. The depot of Clause 1, wherein the analgesic in the therapeuticregion comprises at least 50% of the total weight of the depot.

3. The depot of Clause 1 or Clause 2, wherein the depot is configured torelease the analgesic at the treatment site for no less than 14 days.

4. The depot of Clause 3, wherein about 20% to about 50% of theanalgesic is released in the first about 3 to about 5 days of the 14days, and wherein at least 80% of the remaining analgesic is released inthe last 11 days of the 14 days.

5. The depot of Clause 3, wherein about 20% to about 40% of theanalgesic is released in the first 3 days of the 14 days, and wherein atleast 80% of the remaining analgesic is released in the last 11 days ofthe 14 days.

6. The depot of any one of Clauses 3 to 5, wherein at least 90% of theremaining analgesic is released in the last 11 days of the 14 days.

7. The depot of any one of Clauses 3 to 6, wherein no more than 15% ofthe amount of analgesic is released in the first 2 days of the 14 days.

8. The depot of any one of Clauses 3 to 7, wherein no more than 20% ofthe amount of analgesic is released in the first 2 days of the 14 days.

9. The depot of any one of Clauses 3 to 8, wherein no more than 25% ofthe amount of analgesic is released in the first 3 days of the 14 days.

10. The depot of any one of Clauses 3 to 9, wherein no more than 30% ofthe amount of analgesic is released in the first 3 days of the 14 days.

11. The depot of any one of Clauses 1 to 11, wherein the depot isconfigured to release the analgesic at a first rate for a first periodof time and at a second rate for a second period of time.

12. The depot of Clause 12, wherein the first rate is greater than thesecond rate.

13. The depot of Clause 12, wherein the first period of time is greaterthan the second period of time.

14. The depot of Clause 12, wherein the first period of time is lessthan the second period of time.

15. The depot of any one of Clauses 1 to 14, wherein the depot isconfigured to release at least 90% of the analgesic in the therapeuticregion within 14 days.

16. The depot of any one of Clauses 1 to 15, wherein the depot isconfigured to release about 100 mg to about 500 mg of analgesic to thetreatment site per day.

17. The depot of any one of Clauses 1 to 16, wherein the depot isconfigured to release about 100 mg to about 400 mg of analgesic to thetreatment site per day.

18. The depot of any one of Clauses 1 to 17, wherein the depot isconfigured to release about 100 mg to about 300 mg of analgesic to thetreatment site per day.

19. The depot of any one of Clauses 1 to 18, wherein the depot isconfigured to release no more than 300 mg of analgesic per day withinthe first 3 days, and no more than 200 mg per day in the remaining days.

20. The depot of any one of Clauses 1 to 19, wherein the depot isconfigured to release no more than 150 mg of analgesic per day withinthe first 3 days, and no more than 100 mg per day in the remaining days.

21. The depot of any one of Clauses 1 to 20, wherein no more than 400 mgof analgesic is released within any day of the 14 days.

22. The depot of any one of Clauses 1 to 21, wherein no more than 300 mgof analgesic is released within any day of the 14 days.

23. The depot of any one of Clauses 1 to 22, wherein no more than 250 mgof analgesic is released within any day of the 14 days.

24. The depot of any one of Clauses 1 to 23, wherein no more than 200 mgof analgesic is released within any day of the 14 days.

25. The depot of any one of Clauses 1 to 24, wherein no more than 150 mgof analgesic is released within any day of the 14 days.

26. The depot of any one of Clauses 1 to 25, wherein no more than 100 mgof analgesic is released within any day of the 14 days.

27. The depot of any one of Clauses 1 to 26, wherein the depot isconfigured to release the analgesic agent at the treatment site in vivofor no less than 1 day, no less than 2 days, no less than 3 days, noless than 4 days, no less than 5 days, no less than 6 days, no less than7 days, no less than 8 days, no less than 9 days, no less than 10 days,no less than 11 days, no less than 12 days, no less than 13 days, noless than 14 days, no less than 15 days, no less than 16 days, no lessthan 17 days, no less than 18 days, no less than 19 days, no less than20 days, no less than 21 days, no less than 22 days, no less than 23days, no less than 24 days, no less than 25 days, no less than 26 days,no less than 27 days, no less than 28 days, no less than 29 days, noless than 30 days, no less than 40 days, no less than 50 days, no lessthan 60 days, no less than 70 days, no less than 90 days, no less than100 days, no less than 200 days, no less than 300 days, or no less than365 days.

28. The depot of any one of Clauses 1 to 27, wherein the concentrationof the analgesic in the blood plasma of a mammalian patient on day 10 isno less than 70% of the concentration of the analgesic in the bloodplasma of the patient on day 5.

29. The depot of any one of Clauses 1 to 28, wherein the therapeuticregion comprises a covered portion and an exposed portion, wherein thecovered portion is covered by the control region such that, when thedepot is initially positioned at the treatment site in vivo, the controlregion is between the covered portion of the therapeutic region andphysiologic fluids at the treatment site and the exposed portion of thetherapeutic region is exposed to the physiologic fluids.

30. The depot of any one of Clauses 1 to 29, wherein,

-   -   the depot has a total surface area comprising the exposed        surface area of the cover region plus the exposed surface area        of the therapeutic region, and    -   when the depot is initially positioned at the treatment site in        vivo, a ratio of the exposed surface area of the therapeutic        region to the exposed surface area of the cover region is from        about 5% to about 20%, or from about 5% to about 15%, or from        about 5% to about 10%.

31. The depot of Clause 30, wherein the exposed surface area of thecontrol region is less than the exposed surface area of the therapeuticregion.

32. The depot of Clause 30, wherein the exposed surface area of thecontrol region is greater than the exposed surface area of thetherapeutic region.

33. The depot of any one of Clauses 1 to 32, wherein the control regionis a first control region, and wherein the depot comprises a secondcontrol region.

34. The depot of Clause 33, wherein the first control region is disposedat a first side of the therapeutic region and the second control regionis disposed at a second side of the therapeutic region opposite thefirst side.

35. The depot of any one of Clauses 1 to 34, wherein the depot comprisesa plurality of control regions and a plurality of therapeutic regions,and wherein each of the therapeutic regions is separated from anadjacent one of the therapeutic regions by one or more control regions.

36. The depot of Clause 35, wherein each of the therapeutic regions andeach of the control regions is a micro-thin layer.

37. The depot of Clause 35 or Clause 36, wherein the depot comprisesfrom about 2 to about 100 therapeutic regions.

38. The depot of Clause 35 or Clause 36, wherein the depot comprisesfrom about 2 to about 50 therapeutic regions.

39. The depot of Clause 35 or Clause 36, wherein the depot comprisesfrom about 2 to about 10 therapeutic regions.

40. The depot of any one of Clauses 1 to 34, wherein the therapeuticregion is enclosed by the control region such that, when the depot ispositioned at the treatment site in vivo, the control region is betweenthe therapeutic region and physiologic fluids at the treatment site.

41. The depot of any one of Clauses 1 to 40, wherein the control regioncomprises a first control layer and a second control layer.

42. The depot of Clause 41, wherein the second control layer is adjacentto the therapeutic region and the first control layerencapsulates/encloses the therapeutic region and the second controllayer.

43. The depot of Clause 41 or Clause 42, wherein the first control layerand the second control layer together enclose the therapeutic region.

44. The depot of any one of Clauses 41 to 43, wherein the first controllayer is disposed at a first side of the therapeutic region and thesecond control layer is disposed at a second side of the therapeuticregion opposite the first side.

45. The depot of any one of Clauses 41 to 44, wherein the first controllayer comprises a first plurality of sub-layers and the second controllayer comprises a second plurality of sub-layers.

46. The depot of any one of Clauses 41 to 45, wherein the first controllayer includes a first amount of the releasing agent and the secondcontrol layer includes a second amount of the releasing agent differentthan the first amount.

47. The depot of any one of Clauses 41 to 46, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent greater than thefirst concentration.

48. The depot of any one of Clauses 41 to 46, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein the first control layer includes a firstconcentration of the releasing agent and the second control layerincludes a second concentration of the releasing agent less than thefirst concentration.

49. The depot of any one of Clauses 41 to 48, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein

-   the first control layer includes up to 5% by weight of the releasing    agent, up to 10% by weight of the releasing agent, up to 15% by    weight of the releasing agent, up to 20% by weight of the releasing    agent, up to 25% by weight of the releasing agent, up to 30% by    weight of the releasing agent, up to 35% by weight of the releasing    agent, up to 40% by weight of the releasing agent, up to 45% by    weight of the releasing agent, or 50% by weight of the releasing    agent.-   the second control layer includes up to 5% by weight of the    releasing agent, up to 10% by weight of the releasing agent, up to    15% by weight of the releasing agent, up to 20% by weight of the    releasing agent, up to 25% by weight of the releasing agent, up to    30% by weight of the releasing agent, up to 35% by weight of the    releasing agent, up to 40% by weight of the releasing agent, up to    45% by weight of the releasing agent, or up to 50% by weight of the    releasing agent.

50. The depot of any one of Clauses 41 to 49, wherein the second controllayer is positioned between the first control layer and the therapeuticregion, and wherein the first control layer includes a first amount ofthe releasing agent and the second control layer includes a secondamount of the releasing agent, the second amount being at least 2×, atleast 3×, at least 4×, or at least 5× the first amount.

51. The depot of any one of Clauses 1 to 50, wherein a thickness of thecontrol region is less than or equal to 1/50 of a thickness of thetherapeutic region.

52. The depot of any one of Clauses 1 to 50, wherein a thickness of thecontrol region is less than or equal to 1/75 of a thickness of thetherapeutic region.

53. The depot of any one of Clauses 1 to 50, wherein a thickness of thecontrol region is less than or equal to 1/100 of a thickness of thetherapeutic region.

54. The depot of any one of Clauses 1 to 53, wherein the depot is aflexible solid that is structurally capable of being handled by aclinician during the normal course of a surgery without breaking intomultiple pieces and/or losing its general shape.

55. The depot of any one of Clauses 1 to 54, wherein the depot isconfigured to be placed in the knee of a patient and release theanalgesic in vivo for up to 7 days without breaking into multiplepieces.

56. The depot of any one of Clauses 1 to 55, wherein the depot has awidth and a thickness, and wherein a ratio of the width to the thicknessis 21 or greater.

57. The depot of Clause 56, wherein the ratio is 30 or greater.

58. The depot of Clause 56, wherein the ratio is 40 or greater.

59. The depot of any one of Clauses 1 to 58, wherein the depot has asurface area and a volume, and wherein a ratio of the surface area tovolume is at least 1.

60. The depot of any one of Clauses 1 to 59, wherein the diffusionopenings include at least one or more pores and/or one or more channels.

61. The depot of any one of Clauses 1 to 60, wherein the two or moremicro-thin layers of the bioresorbable polymer are bonded via heatcompression to form the therapeutic region.

62. The depot of any one of Clauses 1 to 61, wherein the control regionand the therapeutic region are bonded via heat compression.

63. The depot of any one of Clauses 1 to 62, wherein the control regionand the therapeutic region are thermally bonded.

64. The depot of any one of Clauses 1 to 63, wherein dissolution of thereleasing agent following in vivo placement in the treatment site causesthe control region and the therapeutic region to transition from a stateof lesser porosity to a state of greater porosity to facilitate therelease of the analgesic from the depot.

65. The depot of any one of Clauses 1 to 64, wherein the control regiondoes not include the analgesic at least prior to implantation of thedepot at the treatment site.

66. The depot of any one of Clauses 1 to 64, wherein the control regioncomprises an analgesic different from the analgesic in the therapeuticregion.

66a. The depot of any one of Clauses 1 to 66, wherein the therapeuticregion does not include any releasing agent prior to implantation of thedepot at the treatment site.

67. The depot of any one of Clauses 1 to 66a, wherein the releasingagent is a first releasing agent and the therapeutic region includes asecond releasing agent mixed with the analgesic.

68. The depot of any one of Clauses 1 to 67, wherein the releasing agentis a first releasing agent and the polymer is a first polymer, and thetherapeutic region includes a second releasing agent and a secondpolymer mixed with the analgesic.

69. The depot of any one of Clauses 1 to 68, wherein the first releasingagent is the same as the second releasing agent.

70. The depot of any one of Clauses 1 to 68, wherein the first releasingagent is the different than the second releasing agent.

71. The depot of any one of Clauses 1 to 70, wherein a concentration ofthe first releasing agent within the control region is the greater thana concentration of the second releasing agent within the therapeuticregion.

72. The depot of any one of Clauses 1 to 70, wherein a concentration ofthe first releasing agent within the control region is the less than aconcentration of the second releasing agent within the therapeuticregion.

73. The depot of any one of Clauses 1 to 70, wherein a concentration ofthe first releasing agent within the control region is the same as aconcentration of the second releasing agent within the therapeuticregion.

74. The depot of any one of Clauses 1 to 72, wherein a concentration ofthe first releasing agent within the control region is different than aconcentration of the second releasing agent within the therapeuticregion.

75. The depot of any one of Clauses 1 to 74, wherein the therapeuticregion includes a plurality of microlayers.

76. The depot of any one of Clauses 1 to 75, wherein the mass of theanalgesic comprises at least 50% of the mass of the depot.

77. The depot of any one of Clauses 1 to 76, wherein the ratio of themass of the analgesic in the depot to the depot polymer mass is at least3:1.

78. The depot of any one of Clauses 1 to 76, wherein the ratio of themass of the analgesic in the depot to the depot polymer mass is at least4:1.

79. The depot of any one of Clauses 1 to 76, wherein the ratio of themass of the analgesic in the depot to the depot polymer mass is at least5:1.

80. The depot of any one of Clauses 1 to 76, wherein a ratio of the massof the analgesic in the depot to the depot polymer mass is at least 6:1.

81. The depot of any one of Clauses 1 to 76, wherein a ratio of the massof the analgesic in the depot to the depot polymer mass is at least 7:1.

82. The depot of any one of Clauses 1 to 76, wherein a ratio of the massof the analgesic in the depot to the depot polymer mass is at least 8:1.

83. The depot of any one of Clauses 1 to 76, wherein a ratio of the massof the analgesic in the depot to the depot polymer mass is at least10:1.

84. The depot of any one of Clauses 1 to 76, wherein a ratio of the massof the analgesic in the depot to the depot polymer mass is at least16:1.

85. The depot of any one of Clauses 1 to 84, wherein the therapeuticregion includes at least 60% by weight of the analgesic, 60% by weightof the analgesic, at least 70% by weight of the analgesic, at least 80%by weight of the analgesic, at least 90% by weight of the analgesic, or100% by weight of the analgesic.

86. The depot of any one of Clauses 1 to 84, wherein the depot includesat least 15% by weight of the analgesic, at least 20% by weight of theanalgesic, at least 30% by weight of the analgesic, at least 40% byweight of the analgesic, at least 50% by weight of the analgesic, atleast 60% by weight of the analgesic, at least 70% by weight of theanalgesic, at least 80% by weight of the analgesic, at least 90% byweight of the analgesic, or 100% by weight of the analgesic.

87. The depot of any one of Clauses 1 to 86, wherein the analgesiccomprises at least one of: simple analgesics, local anesthetics, NSAIDsand opioids.

88. The depot of any one of Clauses 1 to 87, wherein the analgesiccomprises a local anesthetic selected from at least one of bupivacaine,ropivacaine, mepivacaine, and lidocaine.

89. The depot of any one of Clauses 1 to 88, further comprising anantibiotic, an antifungal, and/or an antimicrobial, wherein theantibiotic, the antifungal, and/or the antimicrobial is selected from atleast one of amoxicillin, amoxicillin/clavulanate, cephalexin,ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin,sulfamethoxazole/trimethoprim, tetracycline(s), minocycline,tigecycline, doxycycline, rifampin, triclosan, chlorhexidine,penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin,gentamycin, cephalosporin(s), carbapenems, imipenem, ertapenem,antimicrobial peptides, cecropin-mellitin, magainin, dermaseptin,cathelicidin, α-defensins, and α-protegrins, ketoconazole,clortrimazole, miconazole, econazole, intraconazole, fluconazole,bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole,sulconazole, saperconazole, voriconazole, terbinafine, amorolfine,naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin,cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

90. The depot of any one of Clauses 1 to 89, further comprising ananti-inflammatory agent selected from at least one of steroids,prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone andmethylprednisolone, non-steroidal anti-inflammatory drugs (NSAIDs),aspirin, Ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol,celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac,diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac,fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, andCOX-2 inhibitors.

91. The depot of any one of Clauses 1 to 90, further comprising at leastone of: epinephrine, clonidine, transexamic acid.

92. The depot of any one of Clauses 1 to 91, wherein the releasing agentis a non-ionic surfactant.

93. The depot of any one of Clauses 1 to 92, wherein the releasing agenthas hydrophilic properties.

94. The depot of any one of Clauses 1 to 93, wherein the releasing agentis a polysorbate.

95. The depot of any one of Clauses 1 to 94, wherein the releasing agentis Tween 20.

96. The depot of any one of Clauses 1 to 94, wherein the releasing agentis Tween 80.

97. The depot of any one of Clauses 1 to 96, wherein the releasing agentis non-polymeric.

98. The depot of any one of Clauses 1 to 97, wherein the releasing agentis not a plasticizer.

99. The depot of any one of Clauses 1 to 98, wherein the polymer isconfigured to degrade only after substantially all of the analgesic hasbeen released from the depot.

100. The depot of any one of Clauses 1 to 99, wherein the polymer is acopolymer.

101. The depot of any one of Clauses 1 to 99, wherein the polymer is aterpolymer.

102. The depot of any one of Clauses 1 to 101, wherein the polymerincludes at least one of polyglycolide (PGA), polycaprolactone (PCL),poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acids),poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, andpoly(DL-lactide-co-glycolide-co-caprolactone).

103. The depot of any one of Clauses 1 to 102, wherein the polymer isone of poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

104. The depot of any one of Clauses 1 to 102, wherein the polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of60:30:10.

105. The depot of any one of Clauses 1 to 102, wherein the polymer ispoly(DL-lactide-co-glycolide)(PLGA) in a molar ratio of 50:50.

106. The depot of any one of Clauses 1 to 105, wherein the polymer isester-terminated.

107. The depot of any one of Clauses 1 to 102, wherein the polymer is aterpolymer that includes three polymers selected from the following:polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA),poly(DL-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC),polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

108. The depot of any one of Clauses 1 to 107, wherein the polymer is afirst polymer, and the therapeutic region includes a second polymermixed with the analgesic.

109. The depot of Clause 108, wherein the first polymer and the secondpolymer are the same.

110. The depot of Clause 108, wherein the first polymer and the secondpolymer are different.

111. The depot of any one of Clauses 108 to 110, wherein the firstpolymer and/or the second polymer include at least one of polyglycolide(PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA),poly(alpha-hydroxy acids), poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate)(PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate),tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinatepolyphosphazene, polycaprolactone co-butylacrylate, a copolymer ofpolyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer ofpoly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopolpoly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol,poly(DL-lactide-co-glycolide-co-caprolactone).

112. The depot of any one of Clauses 108 to 111, wherein the firstpolymer and/or the second polymer selected from the following:poly(DL-lactide-co-glycolide-co-caprolactone) andpoly(DL-lactide-co-glycolide)(PLGA).

113. The depot of any one of Clauses 108 to 111, wherein the firstpolymer and/or the second polymer ispoly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of60:30:10.

114. The depot of any one of Clauses 108 to 111, wherein the firstpolymer and/or the second polymer is poly(DL-lactide-co-glycolide) andhas a molar ratio of 50:50.

115. The depot of any one of Clauses 108 to 114, wherein the firstpolymer and/or the second polymer is ester-terminated.

116. The depot of any one of Clauses 108 to 111, wherein the firstpolymer and/or the second polymer is a terpolymer that includes threepolymers selected from the following: polyglycolide (PGA),polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylenecarbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), and polyethylene glycol.

117. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 1:1.

118. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 2:1.

119. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 3:1.

120. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 4:1.

121. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 5:1.

122. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 6:1.

123. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 7:1.

124. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 8:1.

125. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 9:1.

126. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 10:1.

127. The depot of any one of Clauses 1 to 116, wherein the ratio of thereleasing agent to the polymer in the control region is at least 15:1.

128. The depot of any one of Clauses 1 to 127, wherein:

-   -   the polymer is a first polymer and the therapeutic region        further includes a second polymer,    -   the depot has a depot polymer mass equivalent to a mass of the        first polymer plus a mass of the second polymer, and    -   a ratio of a mass of the analgesic in the depot to the depot        polymer mass is approximately 1:1.

129. The depot of Clause 128, wherein the first polymer is the same asthe second polymer.

130. The depot of Clause 128, wherein the first polymer is differentthan the second polymer.

131. The depot of any one of Clauses 128 to 130, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 2:1.

132. The depot of any one of Clauses 128 to 130, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 3:1.

133. The depot of any one of Clauses 128 to 130, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass is atleast 4:1.

134. The depot of any one of Clauses 128 to 130, wherein the ratio ofthe mass of the analgesic in the depot to the depot polymer mass isapproximately 5:1.

135. The depot of any one of Clauses 128 to 130, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least6:1.

136. The depot of any one of Clauses 128 to 130, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least7:1.

137. The depot of any one of Clauses 128 to 130, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least8:1.

138. The depot of any one of Clauses 128 to 130, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least10:1.

139. The depot of any one of Clauses 128 to 130, wherein a ratio of themass of the analgesic in the depot to the depot polymer mass is at least16:1.

140. The depot of any one of Clauses 1 to 139, wherein the analgesic isa local anesthetic, and wherein the release of the analgesic to thetreatment site over the five days inhibits the growth of bacteria andfungi.

141. The depot of Clause 140, wherein depot is configured to inhibit thegrowth of bacteria and fungi such that a number of bacteria on the depotis 10×, 20×, 30×, 40×, or 50× less than a number of bacteria present ona comparable depot containing no analgesic.

142. The depot of any one of Clauses 1 to 141, wherein the release ofanalgesic is at a level sufficiently high to create a sensory block,thereby treating postoperative pain, but sufficiently low to avoid amotor block.

143. The depot of any one of Clauses 1 to 142, wherein the release ofthe analgesic provides motor sparing relief from postoperative pain.

144. A depot for sustained, controlled release of a therapeutic agent,comprising:

-   -   a therapeutic region comprising the therapeutic agent;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in        contact with a fluid to form diffusion openings in the control        region; and    -   wherein, when the depot is placed in contact with a fluid, the        depot is configured to release the therapeutic agent into the        surrounding fluid for no less than 14 days, and    -   wherein about 20% to about 50% of the therapeutic agent is        released in the first about 3 to about 5 days of the 14 days,        and wherein at least 80% of the remaining therapeutic agent is        released in the last 11 days of the 14 days.

145. The depot of Clause 144, wherein at least 85% of the remainingtherapeutic agent is released in the last 11 days of the 14 days.

146. The depot of Clause 144, wherein at least 90% of the remainingtherapeutic agent is released in the last 11 days of the 14 days.

147. The depot of Clause 144, wherein at least 95% of the remainingtherapeutic agent is released in the last 11 days of the 14 days.

148. The depot of any one of Clauses 144 to 147, wherein no more than15% of the amount of therapeutic agent is released in the first 2 daysof the 14 days.

149. The depot of any one of Clauses 144 to 147, wherein no more than20% of the amount of therapeutic agent is released in the first 2 daysof the 14 days.

150. The depot of any one of Clauses 144 to 147, wherein no more than25% of the amount of therapeutic agent is released in the first 3 daysof the 14 days.

151. The depot of any one of Clauses 144 to 147, wherein no more than30% of the amount of therapeutic agent is released in the first 3 daysof the 14 days.

152. The depot of any one of Clauses 144 to 147, wherein the releasingagent is configured to dissolve when the depot is placed in contact withphosphate buffered saline to form diffusion openings.

153. A method for treating postoperative pain, comprising:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising (a) a control region        including a bioresorbable polymer and a releasing agent mixed        with the polymer, and (b) a therapeutic region including at        least 50% by weight of an analgesic; and    -   releasing analgesic from the depot to the treatment site for no        less than seven days.

154. The method of Clause 153, further comprising dissolving thereleasing agent at a first rate and degrading the polymer at a secondrate, wherein the first rate is greater than the second rate.

155. The method of Clause 153 or Clause 154, further comprisingdissolving the releasing agent in response to contact between thecontrol region and the physiologic fluids at the treatment site.

156. The method of any one of Clauses 153 to 155, further comprisingcreating diffusion openings in the control region via the dissolution ofthe releasing agent in response to physiologic fluids at the treatmentsite.

157. The method of any one of Clauses 153 to 156, wherein the releasingagent is a first releasing agent and the therapeutic region includes asecond releasing agent, and wherein the method further comprisescreating microchannels in the therapeutic region and the control regionvia dissolution of the first and/or second releasing agents.

158. The method of any one of Clauses 153 to 157, wherein at least someof the microchannels penetrate both the therapeutic region and thecontrol region.

159. The method of any one of Clauses 153 to 158, wherein thetherapeutic region comprises a plurality of microlayers, and wherein atleast some of the microchannels extend through consecutive microlayers.

160. The method of any one of Clauses 153 to 159, wherein the controlregion comprises a first plurality of microlayers and the therapeuticregion comprises a second plurality of microlayers, and wherein at leastsome of the microchannels extend through the first and second pluralityof microlayers.

161. The method of any one of Clauses 153 to 160, further includingincreasing a porosity of the depot via dissolution of the releasingagent.

162. The method of any one of Clauses 153 to 161, wherein the analgesicis released one or more times in substantially discrete doses afterimplantation.

163. The method of any one of Clauses 153 to 162, wherein the analgesicis released continuously for at least seven days after implantation.

164. The method of any one of Clauses 153 to 163, wherein the analgesicis released for no less than 10 days.

165. The method of any one of Clauses 153 to 163, wherein the analgesicis released for no less than 14 days.

166. The method of any one of Clauses 153 to 165, wherein no more than20% of the amount of analgesic is released in the first day of the sevendays.

167. The method of any one of Clauses 153 to 166, further comprisingsecuring the depot to the treatment site via an attachment means.

168. The method of any one of Clauses 153 to 167, wherein the attachmentmeans is coupled to the depot prior to implantation.

169. The method of any one of Clauses 153 to 168, wherein the depot is afirst depot and the method further comprises positioning a second depotat the treatment site.

170. The method of Clause 169, wherein the first and second depotstogether release at least 1400 mg of the analgesic to the treatment siteover a period of no less than seven days.

171. A method for treating postoperative pain associated with orthopedicsurgery with any of the depots of Clauses 1 to 152 and 196 to 198 and/orsystems of Clauses 179 to 195.

172a. A method for treating postoperative pain in a patient followingorthopedic surgery, the method comprising:

-   -   implanting a plurality of depots at a site of the surgery, each        of the depots comprising (a) a control region including a        bioresorbable polymer and a releasing agent mixed with the        polymer, and (b) a therapeutic region including at least 50% by        weight of an analgesic; and    -   releasing analgesic from the depot to the site for no less than        seven days.

172b. A method for treating postoperative pain in a patient followingorthopedic surgery, the method comprising:

-   -   implanting a depot at a site of the surgery, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the site for no less than        seven days.

172c. A method for treating postoperative pain in a patient followingtotal knee arthroplasty, comprising:

-   -   positioning a depot in a knee of the patient, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the patient's knee for no        less than seven days.

172a. The method of Clause 172, wherein the depot is any of the depotsof Clauses 1 to 152 and 196 to 198.

173. The method of Clause 172 or Clause 172a, wherein positioning thedepot comprises placing at least one depot in at least one of:suprapatellar pouch, lateral gutter, medial gutter, posterior capsule,quadricep tendon, skin incision, arthrotomy, adductor canal, saphenousnerve, genicular nerve.

174. The method of any one of Clauses 172 to 173, wherein positioningthe depot comprises positioning at least one depot adjacent at least oneof a saphenous nerve, an adductor canal, and a femoral nerve.

175. The method of any one of Clauses 172 to 174, wherein positioningthe depot comprises intracapsular placement of at least one depot.

176. The method of any one of Clauses 172 to 174, wherein positioningthe depot comprises extracapsular placement of at least one depot.

177. The method of any one of Clauses 172 to 176, wherein positioningthe depot comprises intracapsular placement without interfering witharticulation of the knee.

178. The method of Clause 172, wherein placing at least one depot at atleast one of: suprapatellar pouch, lateral gutter, medial gutter,posterior capsule, quadricep tendon, skin incision, arthrotomy, adductorcanal.

179. A system for treating postoperative pain associated with orthopedicsurgery, the system comprising:

-   -   a plurality of depots, each of which is any of the depots        described in the previous Clauses, wherein the plurality of        depots are configured to be implanted at a treatment site of a        patient and release the analgesic to the treatment site.

180. The system of Clause 179, wherein the depots are configured torelease analgesic to the treatment site for at least 7 days, at least 8days, at least 9 days, at least 10 days, at least 11 days, at least 12days, at least 13 days, or at least 14 days.

181. The system of Clause 180, wherein the depots are configured tocollectively release no more than 250 mg of analgesic per day within thefirst 3 days, and no more than 150 mg per day in the remaining days.

182. A system for treating postoperative pain, comprising:

-   -   a delivery system; and    -   a depot configured to be implanted at a treatment site in vivo        with the delivery system, wherein the depot comprises any of the        depots of Clauses 1 to 152 and 196 to 198.

182a. A system for treating postoperative pain, comprising:

-   -   an attachment means; and    -   a depot configured to be implanted at a treatment site in vivo        and secured at the treatment site via the attachment means,        wherein the depot comprises any of the depots of Clauses 1 to        152 and 196 to 198.

183. The system of Clause 182a, wherein the attachment means is coupledto the depot prior to implantation.

184. The system of Clause 182 or Clause 183, wherein the attachmentmeans is at least one of a suture, a tine, a barb, a hook, and a screw.

185. The system of any one of Clauses 182a to 184, wherein the pain isassociated with orthopedic surgery.

186. The system of any one of Clauses 182a to 185, wherein the pain isassociated with joint replacement surgery.

187. The system of any one of Clauses 182a to 186, wherein the pain isassociated with a knee replacement surgery.

188. The system of Clause 187, wherein the pain is associated with apartial knee replacement surgery.

189. The system of Clause 187, wherein the pain is associated with atotal knee replacement surgery.

190. The system of Clause 187, wherein the pain is associated with arevision surgery of a knee replacement surgery.

191. The system of any one of Clauses 182a to 190, wherein the depot isconfigured to be positioned adjacent at least one of a saphenous nerve,an adductor canal, and a femoral nerve.

192. The system of any one of Clauses 182a to 191, wherein the depot isconfigured to be positioned adjacent at least one of a posterior capsuleof the knee, a superior region of the patella, or an incision into theknee capsule.

193. The system of any one of Clauses 182a to 191, wherein the depot isconfigured to be positioned within the knee capsule within the medialand/or lateral gutters.

194. A system for treating postoperative pain, comprising a deliverysystem and any of the depots of Clauses 1 to 152 and 196 to 198.

195. A system for treating postoperative pain, comprising a plurality ofdepots, any of which comprising any of the depots of Clauses 1 to 152and 196 to 198.

196. A depot for the release of a therapeutic agent to treat or manage aparticular condition or disease, comprising:

-   -   a therapeutic region comprising the therapeutic agent and a        bioresorbable polymer carrier;    -   a control region comprising a bioresorbable polymer layer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve over a first period of time        following in vivo placement to form diffusion openings in the        control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the therapeutic agent        at the treatment site for a second period of time;    -   wherein the second period of time is greater than the first        period of time;    -   wherein following the second period of time the polymer carrier        of the therapeutic region and the polymer layer of the control        region comprise a highly porous polymer structure configured to        degrade in vivo without core acidification.

197. The depot of Clause 196, wherein the highly porous polymerstructure at the end of the second period of time has a mass that is nogreater than 50% of the mass of the depot prior to in vivo placement.

198. The depot of Clause 197, wherein the highly porous polymerstructure is configured to degrade in vivo via surface erosion.

199. A method for treating postoperative pain following a non-orthopedicsurgical procedure, comprising:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising (a) a control region        including a bioresorbable polymer and a releasing agent mixed        with the polymer, and (b) a therapeutic region including at        least 50% by weight of an analgesic;    -   dissolving the releasing agent in response to contact between        the releasing agent and the physiologic fluids, thereby forming        diffusion openings in the control region; and    -   releasing analgesic through the diffusion openings from the        therapeutic region to the treatment site for no less than five        days.

200. The method of Clause 199, wherein the surgical procedure comprisesat least one of: a thoracotomy, an esophageal surgery, a cardiacsurgery, a lung resection, or a thoracic surgery.

201. The method of Clause 200, wherein the treatment site comprises athoracic paravertebral space.

202. The method of Clause 200 or Clause 201, wherein the analgesicreleased from the depot at least partially blocks an intercostal nerve.

203. The method of Clause 199, wherein the surgical procedure comprisesat least one of: a mastectomy, a breast augmentation, a breastreduction, or a breast reconstruction.

204. The method of Clause 203, wherein the treatment site comprises aninfraclavicular space.

205. The method of Clause 203 or Clause 204, wherein the analgesicreleased from the depot at least partially blocks at least one of: anintercostal nerve, a medial pectoral nerve, or a lateral pectoral nerve.

206. The method of Clause 199, wherein the surgical procedure comprisesat least one of: a myomectomy, a Caesarean section, a hysterectomy, anoophorectomy, or a pelvic floor reconstruction.

207. The method of Clause 199, wherein the surgical procedure comprisesat least one of: a proctocolectomy, a pancreatectomy, an appendectomy, ahemorrhoidectomy, a cholecystectomy, a kidney transplant, a nephrectomy,a radical prostatectomy, a gastrectomy, a small bowel resection, asplenectomy, an incisional hernia repair, an inguinal hernia repair, asigmoidectomy, a liver resection, an enterostomy, a rectum resection, akidney stone removal, or a cystectomy.

208. The method of Clause 207, wherein the analgesic released from thedepot at least partially blocks a nerve at or adjacent to a transverseabdominis plane.

209. The method of Clause 199, wherein the surgical procedure comprisesat least one of: a tonsillectomy, a submucosal resection, a rhinoplasty,a sinus surgery, an inner ear surgery, a parotidectomy, or asubmandibular gland surgery.

210. The method of Clause 199, wherein the surgical procedure comprisesat least one of: a dentoalveolar surgery, a dental implant, anorthognathic surgery, a temporomandibular joint (TMJ) surgery, or anoral reconstruction surgery.

211. The method of Clause 199, wherein the surgical procedure comprisesa tumor resection.

212. The method of Clause 199, wherein the surgical procedure comprisesliposuction.

213. The method of any one of Clauses 199 to 212, further comprisingdissolving the releasing agent at a first rate and degrading the polymerat a second rate, wherein the first rate is greater than the secondrate.

214. The method of any one of Clauses 199 to 213, wherein the analgesicis released for no less than 10 days.

215. The method of any one of Clauses 199 to 214, wherein the analgesicis released for no less than 14 days.

216. The method of any one of Clauses 199 to 215, wherein no more than20% of the amount of analgesic is released in the first day of the fivedays.

217. The method of any one of Clauses 199 to 216, further comprisingsecuring the depot to the treatment site via an attachment means.

218. The method of Clause 217, wherein the attachment means is coupledto the depot prior to implantation.

219. The method of any one of Clauses 199 to 218, wherein the depot is afirst depot and the method further comprises positioning a second depotat the treatment site.

220. The method of Clause 219, wherein the first and second depotstogether release at least 1400 mg of the analgesic to the treatment siteover a period of no less than seven days.

221. The method of any one of Clauses 199 to 220, wherein no more than400 mg of the therapeutic agent is released within any day of the fivedays.

222. A method for treating postoperative pain following a non-orthopedicsurgical procedure, comprising:

-   -   positioning a depot at a treatment site in vivo having        physiologic fluids, the depot comprising (a) a control region        including a bioresorbable polymer and a releasing agent mixed        with the polymer, and (b) a therapeutic region including at        least 50% by weight of an analgesic; and    -   releasing analgesic from the depot to the treatment site for no        less than five days.

223. The method of Clause 222, wherein the surgical procedure comprisesat least one of: a thoracotomy, an esophageal surgery, a cardiacsurgery, a lung resection, or a thoracic surgery.

224. The method of Clause 223, wherein the treatment site comprises athoracic paravertebral space.

225. The method of Clause 223 or 224, wherein the analgesic releasedfrom the depot at least partially blocks an intercostal nerve.

226. The method of Clause 222, wherein the surgical procedure comprisesat least one of: a mastectomy, a breast augmentation, a breastreduction, or a breast reconstruction.

227. The method of Clause 226, wherein the treatment site comprises aninfraclavicular space.

228. The method of Clause 226 or 227, wherein the analgesic releasedfrom the depot at least partially blocks at least one of: an intercostalnerve, a medial pectoral nerve, or a lateral pectoral nerve.

229. The method of Clause 222, wherein the surgical procedure comprisesat least one of: a myomectomy, a caesarean section, a hysterectomy, anoophorectomy, or a pelvic floor reconstruction.

230. The method of Clause 222, wherein the surgical procedure comprisesat least one of: a proctocolectomy, a pancreatectomy, an appendectomy, ahemorrhoidectomy, a cholecystectomy, a kidney transplant, a nephrectomy,a radical prostatectomy, a gastrectomy, a small bowel resection, asplenectomy, an incisional hernia repair, an inguinal hernia repair, asigmoidectomy, a liver resection, an enterostomy, a rectum resection, akidney stone removal, or a cystectomy.

231. The method of Clause 230, wherein the analgesic released from thedepot at least partially blocks a nerve at or adjacent to a transverseabdominis plane.

232. The method of Clause 222, wherein the surgical procedure comprisesat least one of: a tonsillectomy, a submucosal resection, a rhinoplasty,a sinus surgery, an inner ear surgery, a parotidectomy, or asubmandibular gland surgery.

233. The method of Clause 222, wherein the surgical procedure comprisesat least one of: a dentoalveolar surgery, a dental implant, anorthognathic surgery, a temporomandibular joint (TMJ) surgery, or anoral reconstruction surgery.

234. The method of Clause 222, wherein the surgical procedure comprisesa tumor resection.

235. The method of Clause 222, wherein the surgical procedure comprisesliposuction.

236. A method for treating postoperative pain following a surgicalprocedure involving a patient's chest, the method comprising:

-   -   positioning a depot proximate to an intercostal nerve at a        treatment site having physiologic fluids, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the intercostal nerve for        no less than five days.

237. The method of Clause 236, wherein the surgical procedure comprisesat least one of: a thoracotomy, an esophageal surgery, a cardiacsurgery, a lung resection, or a thoracic surgery.

238. The method of Clause 236 or 237, wherein the treatment sitecomprises a thoracic paravertebral space.

239. A method for treating postoperative pain following a surgicalprocedure involving a patient's breast, the method comprising:

-   -   positioning a depot proximate to an intercostal and/or pectoral        nerve at a treatment site having physiologic fluids, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the intercostal and/or        pectoral nerve for no less than five days.

240. The method of Clause 239, wherein the surgical procedure comprisesat least one of: a mastectomy, a breast augmentation, a breastreduction, or a breast reconstruction.

241. The method of Clause 239 or 240, wherein the treatment sitecomprises an intraclavicular space.

242. A method for treating postoperative pain following a general,abdominal, or urological surgical procedure, the method comprising:

-   -   positioning a depot proximate to a transverse abdominis plane at        a treatment site having physiologic fluids, the depot        comprising (a) a control region including a bioresorbable        polymer and a releasing agent mixed with the polymer, and (b) a        therapeutic region including at least 50% by weight of an        analgesic; and    -   releasing analgesic from the depot to the intercostal and/or        pectoral nerve for no less than five days.

243. The method of Clause 242, wherein the surgical procedure comprisesat least one of: a proctocolectomy, a pancreatectomy, an appendectomy, ahemorrhoidectomy, a cholecystectomy, a kidney transplant, a nephrectomy,a radical prostatectomy, a gastrectomy, a small bowel resection, asplenectomy, an incisional hernia repair, an inguinal hernia repair, asigmoidectomy, a liver resection, an enterostomy, a rectum resection, akidney stone removal, or a cystectomy.

244. A depot for sustained, controlled release of a therapeutic agent,the depot comprising:

a therapeutic region comprising the therapeutic agent; and

a control region comprising a bioresorbable polymer and a releasingagent mixed with the polymer, wherein the releasing agent is configuredto dissolve when the depot is placed in vivo to form diffusion openingsin the control region;

wherein the depot is configured such that, following submersion of thedepot in buffer solution for seven days, the flexural strength of thedepot decreases by no more than 75%.

245. The depot of Clause 244, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 70%.

246. The depot of Clause 244, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 65%.

247. The depot of Clause 244, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 60%.

248. The depot of Clause 244, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 55%.

249. The depot of Clause 244, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 50%.

250. The depot of Clause 244, wherein the depot is configured such that,following submersion of the depot in buffer solution for seven days, theflexural strength of the depot decreases by no more than 45%.

251. A depot for sustained, controlled release of a therapeutic agent,the depot comprising:

-   -   a therapeutic region comprising the therapeutic agent; and    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured such that, following submersion        of the depot in buffer solution until approximately 75% of the        therapeutic agent by weight has been released, the flexural        strength of the depot decreases by no more than 75%.

252. The depot of Clause 251, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 70%.

253. The depot of Clause 251, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 65%.

254. The depot of Clause 251, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 60%.

255. The depot of Clause 251, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 55%.

256. The depot of Clause 251, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 50%.

257. The depot of Clause 251, wherein the depot is configured such that,following submersion of the depot in buffer solution until approximately75% of the therapeutic agent by weight has been released, the flexuralstrength of the depot decreases by no more than 45%.

258. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 14 days, and wherein about 20%        to about 40% of the analgesic is released in the first 3 days of        the 14 days, and wherein at least 80% of the remaining analgesic        is released in the last 11 days of the 14 days.

259. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the control region does not include the analgesic at        least prior to implantation of the depot at the treatment site.

260. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region; and    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days,    -   wherein the control region comprises an analgesic different from        the analgesic in the therapeutic region.

261. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the releasing agent is a first releasing agent and the        therapeutic region includes a second releasing agent mixed with        the analgesic.

262. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the releasing agent is a first releasing agent and the        polymer is a first polymer, and the therapeutic region includes        a second releasing agent and a second polymer mixed with the        analgesic.

263. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein a thickness of the control region is less than or equal        to 1/50 of a thickness of the therapeutic region.

264. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein a thickness of the control region is less than or equal        to 1/75 of a thickness of the therapeutic region.

265. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein a thickness of the control region is less than or equal        to 1/100 of a thickness of the therapeutic region.

266. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic; and    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region,    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days, and    -   wherein the first control layer includes a first amount of the        releasing agent and the second control layer includes a second        amount of the releasing agent different than the first amount.

267. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising:

-   -   a therapeutic region comprising the analgesic;    -   a control region comprising a bioresorbable polymer and a        releasing agent mixed with the polymer, wherein the releasing        agent is configured to dissolve when the depot is placed in vivo        to form diffusion openings in the control region;    -   wherein the depot is configured to be implanted at a treatment        site in vivo and, while implanted, release the analgesic at the        treatment site for no less than 3 days,    -   wherein the depot has a total surface area comprising the        exposed surface area of the cover region plus the exposed        surface area of the therapeutic region, and    -   wherein, when the depot is initially positioned at the treatment        site in vivo, a ratio of the exposed surface area of the        therapeutic region to the exposed surface area of the cover        region is from about 5% to about 20%, or from about 5% to about        15%, or from about 5% to about 10%.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 depicts the release of bupivacaine hydrochloride over time from aXaracoll® sponge.

FIG. 2 is an isometric view of a depot configured in accordance with thepresent technology.

FIG. 3 depicts the release profile over time of one or more depots ofthe present technology.

FIG. 4 is an isometric view of a depot in accordance with someembodiments of the present technology.

FIG. 5 is an isometric view of a depot in accordance with someembodiments of the present technology.

FIG. 6 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 7 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 8 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 9A is an isometric view of a depot in accordance with someembodiments of the present technology.

FIG. 9B is a cross-sectional view of the depot shown in FIG. 9A.

FIG. 10 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 11 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 12 is a cross-sectional view of a depot in accordance with someembodiments of the present technology.

FIG. 13 is an isometric view of a depot in accordance with someembodiments of the present technology.

FIGS. 14A-H are depots having different cross-sectional areas and shapesin accordance with the present technology.

FIG. 15 depicts the maximum flexural load of an implant over time fromtesting performed on implant samples submerged in buffered solution.

FIGS. 16A-16E depict various depot embodiments including a base regionand/or a delayed release region in accordance with the technology.

FIG. 17 is a schematic representation of core acidification of the priorart.

FIG. 18 is a scanning electron microscope image of a polymer tablet ofthe prior art after 20 days of degradation.

FIG. 19A is a schematic representation of the degradation of the depotsof the present technology.

FIGS. 19B and 19C are scanning electron microscope (“SEM”) images ofcross-sections of depots of the present technology at differenttimepoints during degradation.

FIG. 20 depicts the in vitro release profile for the depots as describedin Example 1, in accordance with the present technology.

FIG. 21 depicts the in vitro release profile for the depots as describedin Example 2A, in accordance with the present technology.

FIG. 22 depicts the in vitro release profile for the depots as describedin Example 2B, in accordance with the present technology.

FIG. 23 depicts the in vitro release profile for the depots as describedin Example 3, in accordance with the present technology.

FIG. 24A shows the in vivo blood plasma bupivacaine concentration overtime for a rabbit implanted with the depots as described in Example 4,in accordance with the present technology.

FIG. 24B depicts the in vitro release profile over time for the sampledepots as described in Example 4, in accordance with the presenttechnology.

FIG. 24C shows the in vivo blood plasma bupivacaine concentration overtime for a rabbit implanted with the depots as described in Example 4,in accordance with the present technology.

FIG. 24D depicts the in vitro release profile over time of the sampledepots as described in Example 4, in accordance with the presenttechnology.

FIG. 25 shows the in vivo blood plasma bupivacaine concentration overtime for a canine implanted with the depots as described in Example 5,in accordance with the present technology.

FIG. 26A shows the in vivo blood plasma bupivacaine concentration overtime for a sheep implanted with the depots as described in Example 6, inaccordance with the present technology.

FIG. 26B shows the in vivo synovial bupivacaine concentration over timefor a sheep implanted with the depots as described in Example 6, inaccordance with the present technology.

FIG. 26C is a plot depicting the blood plasma bupivacaine concentrationversus the synovial bupivacaine concentration over time for a sheepimplanted with the depots as described in Example 6, in accordance withthe present technology.

FIGS. 27A and 27B illustrate common locations within a patient that maybe sites where surgery is conducted and locations where the depot can beadministered.

FIG. 28 is a table showing common surgical procedures for which thedepots of the present technology may be utilized for treatingpostoperative pain. FIG. 28 also shows nerve targets and anatomicalaccess/placement associated with the different surgeries.

FIGS. 29A-29C are anterior, lateral, and medial views of a human knee,showing the location of the nerves innervating the knee.

FIG. 30A is a splayed view of a human knee exposing the intracapsularspace and identifying potential locations for positioning one or moredepots.

FIG. 30B is a splayed view of a human knee exposing the intracapsularspace and showing several depots positioned within for treatingpostoperative pain.

FIGS. 31A and 31B show anterior and posterior, extracapsular views of ahuman knee, showing the location of the nerves innervating the knee atan extracapsular location.

FIG. 32 is an anterior view of a partially-splayed human knee, showingan extracapsular space and showing several depots of the presenttechnology positioned at the extracapsular space for treatingpostoperative pain.

DETAILED DESCRIPTION

The present technology relates to implantable depots for the sustained,controlled release of therapeutic agents, and associated devices,systems, and methods of use. An overview of the depots of the presenttechnology and associated release kinetics are described below withreference to FIGS. 2 and 3 and Section I. Selected embodiments of thedepots of the present technology are described below with reference toFIGS. 4-19C and Section II. Selected examples of the depots of thepresent technology and associated release profiles are described belowwith reference to FIGS. 20-26C and Section III. Selected devices,systems, and methods for using the depots of the present technology fortreating postoperative pain associated with orthopedic surgery aredescribed below with reference to FIGS. 27A-32 and Section IV. Selecteddevices, systems, and methods for using the depots of the presenttechnology for treating postoperative pain associated with othersurgeries are described below at Section V.

I. OVERVIEW

Disclosed herein are implantable depots and associated devices, systems,and methods for treating (i.e., preventing, reducing, and/oreliminating) postoperative pain via sustained, controlled release of atherapeutic agent while the depot is implanted at a treatment site invivo. Many embodiments of the present technology comprise one or moredepots configured to be implanted at or near a surgical site of apatient to treat pain following a surgery. While implanted in vivo, thedepot(s) are configured to release a therapeutic agent (such as ananalgesic) to the surgical site in a controlled, prescribed manner forat least 3 days following implantation.

As used herein, a “depot” comprises the composition in which at leastone therapeutic agent is administered to the body of a patient. Thus, adepot may comprise a physical structure or carrier to facilitateimplantation and retention in a desired site (e.g., tissue at theintracapsular and/or extracapsular space of a knee joint). The depotalso comprises the therapeutic agent itself. A “depot” includes but isnot limited to films, sheets, strips, ribbons, capsules, coatings,matrices, wafers, pills, pellets, or other pharmaceutical deliveryapparatus or a combination thereof. Moreover, as used herein, “depot”may refer to a single depot, or may refer to multiple depots. As anexample, the statement “The depot may be configured to release 2 g oftherapeutic agent to a treatment site” describes (a) a single depot thatis configured to release 2 g of therapeutic agent to a treatment site,and (b) a plurality of depots that collectively are configured torelease 2 g of therapeutic agent to a treatment site.

FIG. 2 is an isometric view of an implantable depot 100 in accordancewith several embodiments of the present technology. The depot 100 may bea thin, multi-layered polymer film configured to be implanted at atreatment site comprising a therapeutic region 200 containing atherapeutic agent (such as an analgesic), and a control region 300configured to regulate the release of the therapeutic agent from thedepot 100 in a controlled and sustained manner. The depot 100 mayinclude a high therapeutic payload of the therapeutic agent, especiallyas compared to other known films of equal thickness or polymer weightpercentage. For example, in some embodiments, the depot 100 comprises atleast 50% by weight of the therapeutic agent.

The control region 300 may comprise a bioresorbable polymer and areleasing agent mixed with the polymer, and the therapeutic region 200may comprise a bioresorbable polymer and a releasing agent mixed withthe polymer and the therapeutic agent. The control region 300 mayoptionally include a therapeutic agent, or the control region mayinclude no therapeutic agent at all. As detailed in Section II below, insome embodiments the therapeutic region 200 and/or the control region300 may have different constituents and/or formulations.

When a fluid contacts the depot 100, the releasing agent dissolveswithin the surrounding polymer of the control region 300 and/ortherapeutic region 200 faster than the polymer degrades. As thereleasing agent dissolves, the space vacated by the dissolved releasingagent forms diffusion openings (e.g., channels, voids, pores, etc.) inthe surrounding polymer region. The concentration and type of releasingagent, among other parameters, can be selected to regulate the releaseof the therapeutic agent from the therapeutic region 200 and through thecontrol region 300 into the surrounding fluid at a controlled dosagerate over a desired period of time.

As shown in FIG. 2, at least a portion of the control region 300 may bedisposed on or adjacent the therapeutic region 200 such that, when thedepot 100 is initially positioned in vivo, the control region 300 isbetween at least a portion of the therapeutic region 200 and physiologicfluids at the treatment site. For example, the control region 300 cancover all or a portion of one or more sides or edges of the therapeuticregion 200. When the depot 100 is exposed to physiologic fluids, thetherapeutic agent elutes from the exposed surfaces of the therapeuticregion 200 and through the control region 300 by way of the diffusionopenings created by dissolution of the releasing agent. In general, thetherapeutic agent elutes from the exposed surfaces of the therapeuticregion 200 at a faster (e.g., greater) rate than through the controlregion 300. As a result, the control region 300 prolongs the release ofthe therapeutic agent from the therapeutic region 200 to provide forlonger release times and regulates the dosage rate to provide thedesired degree of pain relief and avoid complications related tooverdosing.

The depot of the present technology is configured to release atherapeutic agent in a highly controlled, predetermined manner that isspecifically tailored to the medical condition being treated and thetherapeutic agent used. As described in greater detail below in SectionII, the release kinetics of the depots may be customized for aparticular application by varying one or more aspects of the depot'scomposition and/or structure, such as the shape and size of the depot;the exposed surface area of the therapeutic region 200; the type ofpolymer (in the therapeutic region 200 and/or in the control region300); the weight percentage of the therapeutic agent, the polymer,and/or the releasing agent (within a particular region or generallythroughout the depot 100); and the composition of the therapeutic region200 and the control region 300.

As shown in FIG. 3, in many embodiments the depot 100 (or a system ofdepots 100) is configured to release a disproportionately larger volumeof a therapeutic agent per day for a first period of time than for alonger second period of time. In some embodiments, the depot 100 (or asystem of depots 100) is configured to release the therapeutic agent forat least 14 days post-implantation (or post-immersion in a fluid), wherea controlled burst of about 20% to about 50% of the therapeutic agentpayload is released in the first 3-5 days, and at least 80% of theremaining therapeutic agent payload is released at a slower rate overthe last 10-11 days. In some embodiments, at least 90% of thetherapeutic agent payload is released by the end of 14 days.

A two-stage, second-order release profile—such as that shown in FIG.3—may be especially beneficial in the context of treating pain resultingfrom a total knee arthroplasty (“TKA”). TKA patients typicallyexperience the greatest pain within the first 1-3 days following surgery(clinically referred to as “acute pain”) with increasingly less painover the next 7-10 days (clinically referred to as “subacute pain”). Theacute period often overlaps or coincides with the patient's inpatientcare (usually 1-3 days), and the subacute period generally begins whenthe patient is discharged and returns home. The two-stage, second-orderrelease profile shown in FIG. 3 is also beneficial for other surgicalapplications, such as other orthopedic applications (e.g., ligamentrepair/replacement and other damage to the knee, shoulder, ankle, etc.)or non-orthopedic surgical applications. Excessive pain following anysurgery may extend inpatient care, cause psychological distress,increase opioid consumption, and/or impair patient participation inphysical therapy, any of which may prolong the patient's recovery and/ormitigate the extent of recovery. Pain relief during the subacute periodmay be particularly complicated to manage, as patient compliance withthe prescribed pain management regimen drops off when patientstransition from an inpatient to home environment.

To address the foregoing challenges in post-surgical pain management,the depot 100 (or depot system comprising multiple depots 100) of thepresent technology may have a release profile tailored to meet the painmanagement needs specific to the acute and subacute periods. Forexample, to address the greater acute pain that occurs immediatelyfollowing surgery, the depot 100 may be configured to release thetherapeutic agent at a faster rate for the first 3-5 days afterimplantation (as shown in FIG. 3) compared to a subsequent period of9-11 days. In some embodiments, the depot 100 may deliver a localanesthetic at a rate of from about 150 mg/day to about 400 mg/day duringthis first, acute period. To address the diminishing pain during thesubacute period, the depot 100 may be configured to release thetherapeutic agent at a slower rate for the remaining 9-11 days. In someembodiments, the depot 100 may deliver a local anesthetic at a rate offrom about 50 mg/day to about 250 mg/day during this second, subacuteperiod. In some embodiments, the rate of release continuously decreasesthroughout the first period and/or the second period.

The release profile of the depot 100 may be tuned to release atherapeutic agent for other durations and/or at other release rates byadjusting the structure, composition, and the process by which the depotis manufactured. For example, in some embodiments the depot 100 may beconfigured to release the therapeutic agent at a constant ratethroughout the entire duration of release. In particular embodiments,the depot 100 may be configured to release the therapeutic agent at aconstant rate for a first period of time and at a non-constant rate fora second period of time (which may occur before or after the firstperiod of time).

In some embodiments, the depot 100 is configured to release no more than20%, no more than 25%, no more than 30%, no more than 35%, no more than40%, no more than 45%, no more than 50%, no more than 55%, no more than60%, no more than 65%, or no more than 70% of the therapeutic agent inthe first day, 2 days, 3 days, 4 days, 5 days, 6 days, 8 days, 9 days,10 days, 11 days, 12 days, or 13 days of the duration of release, andwherein at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or 100% of the remaining therapeutic agent is released in theremaining days of the duration of release. The intended duration ofrelease may be at least 1 day, at least 2 days, at least 3 days, atleast 4 days, at least 5 days, at least 6 days, at least 7 days, atleast 8 days, at least 9 days, at least 10 days, at least 11 days, atleast 12 days, at least 13 days, at least 14 days, at least 15 days, atleast 16 days, at least 17 days, at least 18 days, at least 19 days, atleast 20 days, at least 21 days, at least 22 days, at least 23 days, atleast 24 days, at least 25 days, at least 26 days, at least 27 days, atleast 28 days, at least 29 days, or at least 30 days.

In some embodiments, the depot 100 is configured to release at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% ofthe therapeutic agent in the depot 100 within the intended duration oftreatment. The intended duration of treatment may be at least 1 day, atleast 2 days, at least 3 days, at least 4 days, at least 5 days, atleast 6 days, at least 7 days, at least 8 days, at least 9 days, atleast 10 days, at least 11 days, at least 12 days, at least 13 days, atleast 14 days, at least 15 days, at least 16 days, at least 17 days, atleast 18 days, at least 19 days, at least 20 days, at least 21 days, atleast 22 days, at least 23 days, at least 24 days, at least 25 days, atleast 26 days, at least 27 days, at least 28 days, at least 29 days, atleast 30 days, at least 40 days, at least 50 days, at least 60 days, atleast 70 days, at least 90 days, at least 100 days, at least 200 days,at least 300 days, or at least 365 days.

In some embodiments, the depot 100 is configured to release from about50 mg/day to about 600 mg/day, 100 mg/day to about 500 mg/day, or fromabout 100 mg/day to about 400 mg/day, or from about 100 mg/day to about300 mg/day of the therapeutic agent to the treatment site. In general,the release rate can be selected to deliver the desired dosage toprovide the extent of pain relief needed at a given time after thesurgical procedure, control toxicity, and deliver the therapeutic agentfor a sufficient period of time for pain relief.

In some embodiments, the depot 100 is configured to release from about50 mg/day to about 600 mg/day, from about 100 mg/day to about 500mg/day, or from about 100 mg/day to about 400 mg/day, or from about 100mg/day to about 300 mg/day of the therapeutic agent to the treatmentsite within a first period of release. The depot 100 can further beconfigured to release from about 500 mg/day to about 600 mg/day, about100 mg/day to about 500 mg/day, or from about 100 mg/day to about 400mg/day, or from about 100 mg/day to about 300 mg/day of the therapeuticagent to the treatment site within a second period of release. Therelease rate during the first period may be the same as, different than,less than, or greater than the release rate during the second period.Moreover, the first period may be longer or shorter than the secondperiod. The first period may occur before or after the second period.

In some embodiments, the depot 100 is configured to release no more than50 mg, no more than 100 mg, no more than 150 mg, no more than 200 mg, nomore than 250 mg, no more than 300 mg, no more than 350 mg, no more than400 mg, no more than 450 mg, no more than 500 mg, no more than 600 mg,no more than 700 mg, no more than 800 mg, no more than 900 mg, or nomore than 1000 mg of the therapeutic agent within any day of a firstperiod of release. This may be useful for providing different degrees ofpain relief at different times after the surgical procedure, and it mayalso be useful to control toxicity. In such embodiments, the depot 100may be configured to release no more than 50 mg, no more than 100 mg, nomore than 150 mg, no more than 200 mg, no more than 250 mg, no more than300 mg, no more than 350 mg, no more than 400 mg, no more than 450 mg,no more than 500 mg, no more than 600 mg, no more than 700 mg, no morethan 800 mg, no more than 900 mg, or no more than 1000 mg of thetherapeutic agent within any day of a second period of release. Thefirst period of release and/or the second period of release may be 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26days, 27 days, 28 days, 29 days, or 30 days. The depot 100 may beconfigured to release the therapeutic agent at a first rate during thefirst period and at a second rate during the second period. The firstrate may be the same as, different than, less than, or greater than thesecond rate. Moreover, the first period may be longer or shorter thanthe second period. The first period may come before or after the secondperiod.

In some embodiments, the depot 100 is configured to release no more than50 mg, no more than 100 mg, no more than 150 mg, no more than 200 mg, nomore than 250 mg, no more than 300 mg, no more than 350 mg, no more than400 mg, no more than 450 mg, no more than 500 mg, no more than 600 mg,no more than 700 mg, no more than 800 mg, no more than 900 mg, or nomore than 1000 mg of therapeutic agent within any day of the duration ofrelease.

In some embodiments, the depot 100 is configured to release thetherapeutic agent at a treatment site in vivo and/or in the presence ofone or more fluids for no less than 1 day, no less than 2 days, no lessthan 3 days, no less than 4 days, no less than 5 days, no less than 6days, no less than 7 days, no less than 8 days, no less than 9 days, noless than 10 days, no less than 11 days, no less than 12 days, no lessthan 13 days, no less than 14 days, no less than 15 days, no less than16 days, no less than 17 days, no less than 18 days, no less than 19days, no less than 20 days, no less than 21 days, no less than 22 days,no less than 23 days, no less than 24 days, no less than 25 days, noless than 26 days, no less than 27 days, no less than 28 days, no lessthan 29 days, no less than 30 days, no less than 40 days, no less than50 days, no less than 60 days, no less than 70 days, no less than 90days, no less than 100 days, no less than 200 days, no less than 300days, or no less than 365 days.

II. SELECTED DEPOT EMBODIMENTS

The release kinetics of the depots of the present technology may betuned for a particular application by varying one or more aspects of thedepot's structure, such as the exposed surface area of the therapeuticregion 200, the porosity of the control region 300 during and after thereleasing agent dissolves, the concentration of the therapeutic agent inthe therapeutic region, the post-manufacturing properties of thepolymer, the structural integrity of the depots to avoid a suddenrelease of the therapeutic agent, the relative thicknesses of thetherapeutic region 200 compared to the control region 300, and otherproperties of the depots. Several embodiments of depots of the presenttechnology combine one or more of these properties in a manner thatproduces exceptional two-phase release profiles in animal studies thatsignificantly outperform existing injectable or implantable systems,while also overcoming the shortcomings of disclosed prophetic devices.For example, several embodiments have exhibited two-phase releaseprofiles that deliver an adequate mass of therapeutic agent to treatpain associated with joint replacement surgery or other applicationsover a 14-day period while maintaining sufficient structural integrityto withstand the forces of a joint to avoid a sudden release of too muchtherapeutic agent. This surprising result enables depots of the presenttechnology to at least reduce, if not replace, opioids and/or enhanceother existing pain relief systems for orthopedic surgical applications,non-orthopedic surgical applications, and for other applications (e.g.,oncological).

For example, the release profile can be tuned by, at least in part,controlling the amount of exposed surface area of the therapeutic region200 because depots having a therapeutic region 200 covered onlypartially by a control region 300 (see, for example, FIGS. 2, 4-8, and13) will generally release a higher proportion of the total payload overa shorter period of time as compared to embodiments where thetherapeutic region 200 is completely encapsulated by the control region300 (see, for example, FIGS. 9A-12). More specifically, depot designshaving a therapeutic region 200 with exposed edges will typicallyrelease the therapeutic agent at a high, substantially linear rate for afirst period of time and then at a lower, substantially linear rate fora second period of time. Alternatively, depot designs having atherapeutic region 200 with edges that are substantially covered by oneor more control regions 300 may achieve a zero-order release such thatthe release of the payload of therapeutic agent is at substantially thesame rate.

As shown in FIG. 4, in some embodiments the depot 100 may comprise amulti-layer polymer film having a therapeutic region 200 and first andsecond control regions 300 a, 300 b positioned at opposite sides 100 a,100 b of the therapeutic region 200. The depot 100 may be in the form ofa flexible, rectangular strip having a length L, a width W, and a heightH (or thickness). In some embodiments, the depot 100 has a length L offrom about 20 mm to about 30 mm (e.g., about 25 mm, etc.), a width W offrom about 10 mm to about 20 mm (e.g., about 15 mm, etc.), and a heightH of from about 0.4 mm to about 4 mm (e.g., of from about 1 mm to about3 mm, of from about 1 mm to about 2 mm, at least 0.4 mm, at least 0.5mm, at least 0.6 mm, at least 0.7 mm, at least 0.8 mm, at least 0.9 mm,at least 1 mm, at least 1.2 mm, at least 1.4 mm, at least 1.5 mm, atleast 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 2 mm, at leastabout 3 mm, etc.). In some embodiments, the depot 100 may have othershapes and/or dimensions, such as those detailed below.

The control regions 300 a, 300 b may only cover a portion of thetherapeutic region 200 such that a portion of each of the sides (e.g.,sidewall) of the therapeutic region 200 is exposed to physiologic fluidsimmediately upon implantation of the depot 100 in vivo. When the depot100 is exposed to physiologic fluids (or any similar fluid in an invitro setting), the therapeutic agent will elute from the exposedsurfaces 202 (in addition to through the control regions 300 a, 300 b),such that the therapeutic agent is released faster than if thetherapeutic region 200 had no exposed regions. As such, the surface areaof the exposed surfaces 202 may be tailored to provide an initial,controlled burst, followed by a tapering release (for example, similarto that shown at FIG. 3). The initial, more aggressive release of thetherapeutic agent is slowed in part by the control regions 300 a, 300 bthat initially reduce the surface area of the therapeutic region 200exposed to the fluids. Unlike the depots 100 of the present technology,many conventional drug-eluting technologies provide an initial,uncontrolled burst release of drug when exposed to physiologic fluids.Several embodiments of depots of the present technology not only enableenough therapeutic agent to be implanted for several days' or weeks'worth of dosage to achieve a sustained, durable, in vivo pharmacologicaltreatment, but they also release the therapeutic agent as prescribed andthereby prevent a substantial portion of the entire payload beingreleased in an uncontrolled manner that could potentially result incomplications to the patient and/or reduce the remaining payload suchthat there is not enough therapeutic agent remaining in the depot todeliver a therapeutic amount for the remaining duration of release.

In some embodiments, the depot 100 shown in FIG. 4 is configured suchthat about 20% to about 50% of the analgesic is released in the firstabout 3 days to about 5 days of the 14 days, and wherein at least 80% ofthe remaining analgesic is released in the last about 9 days to about 11days of the 14 days. This release profile provides higher dosages of thetherapeutic agent during the acute period after surgery compared to thesubacute period. In some embodiments, the depot 100 shown in FIG. 4 isconfigured to release about 100 mg to about 500 mg of analgesic to thetreatment site per day, and in some cases no more than 400 mg or no morethan 300 mg of analgesic per day within the first 3 days of implantationand no more than 200 mg per day in the remaining days. Additionally,some embodiments of the depot shown in FIG. 4 are configured such that athickness of the control regions 300 a and 300 b, either individually orcollectively, is less than or equal to 1/50 of a thickness of thetherapeutic region 200. The thickness of the control regions 300 a and300 b, either individually or collectively, can further be no more than1/75 or 1/100 of the thickness of the therapeutic region 200. Further,the depot 100 shown FIG. 4 can have a ratio of the mass of the analgesicin the depot to the depot polymer mass is at least 16:1, 10:1, 8:1, 7:1,6:1, 5:1, 4:1, 3:1, or 2:1.

Several embodiments of the depot 100 shown in FIG. 4 are also configuredto maintain their structural integrity even after a substantial portionof the releasing agent has eluted from the depot 100. As the releasingagent(s) dissolves and therapeutic agent(s) elutes, the functionalmechanical aspects of the depot 100 may change over time. Suchmechanical aspects include structural integrity, flexural strength,tensile strength, or other mechanical characteristics of the depot. If adepot 100 experiences too much degradation too fast, it may failmechanically and release an undesirable burst of therapeutic agent intothe body. Several embodiments of depots 100 shown in FIG. 4 are loadedwith enough therapeutic agent to deliver 100 mg to 500 mg of thetherapeutic agent per day while still being able to maintain itsstructural integrity such that depot remains largely intact up to atleast 14 days after implantation. For example, the therapeutic agent canbe at least 50%-95% by weight of the total weight of the depot 100before implantation, or 55%-85% by weight of the total weight of thedepot 100 before implantation, or 60%-75% by weight of the total weightof the depot 100 before implantation. A depot can be sufficientlyintact, for example, if it does not fracture into multiple componentpieces with two or more of the resulting pieces being at least 5% of theprevious size of the depot. Alternatively, or additionally, a depot canbe considered to be sufficiently intact if the release rate of thetherapeutic agent does not increase by more than a factor of three ascompared to the release rate of therapeutic agent in a control depotsubmerged in a buffered solution.

Several embodiments of the depot 100 shown in FIG. 4 having one or morecombinations of the parameters described in the preceding paragraphshave provided exceptional results in animal studies as described herein.For example, a depot 100 was configured such that (a) the thickness ofthe control regions 300 a-b were each or collectively less than or equalto 1/50 of the thickness of the therapeutic region 200, (b) the mass oftherapeutic agent payload was sufficient to release about 100 mg toabout 500 mg of analgesic to the treatment site per day, and (c) thestructural integrity was such that the depot remained largely intact forat least 14 days after implantation. These embodiments were able torelease about 20% to about 50% of the analgesic payload in the firstabout 3 days to about 5 days of the 14 days, and then release at least80% of the remaining analgesic payload in the last about 9 days to about11 days of the 14 days. This was unexpected because, at least in part,(a) providing such a large payload of therapeutic agent in thetherapeutic region was expected to cause the depot 100 fail mechanicallyon or before 14 days post-implant, and (b) no disclosed devices hadachieved a release profile wherein about 20% to about 50% of theanalgesic was released in the first about 3 days to about 5 days of the14 days, and then at least 80% of the remaining analgesic was releasedin the last about 9 days to about 11 days of the 14 days.

In some embodiments, one or more control regions 300 of the depot 100may comprise two or more sub-control regions. For example, as shown inFIG. 5, the depot 100 may have a first control region 300 a and a secondcontrol region 300 b, each of which comprises first and secondsub-control regions 302 a, 302 b and 302 c, 302 d, respectively. Thefirst and second control regions 300 a, 300 b and/or one, some or all ofthe sub-control regions 302 a-302 d may have the same or differentamounts of releasing agent, the same or different concentrations ofreleasing agent, the same or different releasing agents, the same ordifferent amounts of polymer, the same or different polymers, the sameor different polymer to releasing agent ratios, and/or the same ordifferent thicknesses. In some embodiments, the concentration of thereleasing agent in the individual outer control sub-regions 302 a, 302 dis less than the concentration of the releasing agent in the individualinner control sub-regions 302 b, 302 c such that the outer portion ofthe collective control region will elute the therapeutic agent moreslowly than the inner portion of the collective control region. In someembodiments, the concentration of the releasing agent in the individualouter control sub-regions 302 a, 302 d is greater than the concentrationof the releasing agent in the individual inner control sub-regions 302b, 302 c. In those embodiments where the control region includes morethan two sub-regions, the concentration of releasing agent persub-region or layer may increase, decrease, or remain constant as thesub-control regions are farther away from the therapeutic region 200.

In certain embodiments, the outer control sub-regions include at least5% by weight of the releasing agent, at least 10% by weight of thereleasing agent, at least 15% by weight of the releasing agent, at least20% by weight of the releasing agent, at least 25% by weight of thereleasing agent, at least 30% by weight of the releasing agent, at least35% by weight of the releasing agent, at least 40% by weight of thereleasing agent, at least 45% by weight of the releasing agent, or atleast 50% by weight of the releasing agent. In some embodiments, theinner control sub-regions include at least 5% by weight of the releasingagent, at least 10% by weight of the releasing agent, at least 15% byweight of the releasing agent, at least 20% by weight of the releasingagent, at least 25% by weight of the releasing agent, at least 30% byweight of the releasing agent, at least 35% by weight of the releasingagent, at least 40% by weight of the releasing agent, at least 45% byweight of the releasing agent, or at least 50% by weight of thereleasing agent. In some embodiments, the outer control sub-regions mayinclude a first amount of the releasing agent and the inner controlsub-regions may include a second amount of the releasing agent, wherethe second amount is at least 200%, at least 300%, at least 400%, or atleast 500% greater than the first amount.

FIGS. 6-8 show depot embodiments having a plurality of alternatingtherapeutic regions 200 and control regions 300 in accordance with thepresent technology. The depot 100 may have two or more control regions300 and/or sub-regions 302 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.),and the depot 100 may have one or more therapeutic regions 200 and/orsub-regions 202 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surroundedby at least one control region 300 and/or sub-region 302. In someembodiments, each of the therapeutic regions 200 may comprise a singlelayer and/or each of the control regions 300 may comprise a singlelayer. In some embodiments, one, some, or all of the therapeutic regions200 may comprise multiple layers and/or one, some, or all of the controlregions 300 may comprise multiple layers. In some embodiments, forexample as shown in FIGS. 6 and 7, two or more sub-regions 302 a-b (FIG.6) and 302 a-b and 302 c-d (FIG. 7) may be adjacent to each otherbetween sub-regions 202 of the therapeutic region 200. Moreover, one ormore of the individual control regions 300 and/or one or more of thetherapeutic regions 200 may have the same or different amounts and/ortypes of releasing agent, and one or more of the therapeutic regions mayhave the same or different amounts and/or types of therapeutic agent.

The embodiments shown in FIGS. 6-8 may be beneficial where thetherapeutic region comprises a large payload of the therapeutic agent(e.g., equivalent to many days, weeks or months of dosage). Theseembodiments may be beneficial because, with such a large payload, shouldthe therapeutic region 200 be exposed to the body abruptly, the entirepayload may be released prematurely, subjecting the patient to anabnormally and undesirably high dose of the therapeutic agent. Forexample, if the integrity of the control region 300 were compromised,the patient may be exposed in vivo to the therapeutic agent at a higherrate than intended, potentially resulting in a clinical complication.Particularly with respect to the administration of local anesthetics(e.g., bupivacaine, ropivacaine, etc.), manufacturing guidelinesrecommend no more than 400 mg should be administered within a 24-hourperiod. However, multiple studies have demonstrated that doses higherthan 400 mg from extended release products are safe due to their slowerrelease over an extended period of time. Regardless, in the event that acontrol region 300 is compromised, it is desirable for the patient to besubjected only to a fraction of the total payload, whereby the fractionto which the patient is exposed if prematurely released would be withinsafety margins for the particular therapeutic agent. The structuralintegrity of the control regions 300, as well as that of the therapeuticregion(s) 200, is an important property for depots with large masses oftherapeutic agents that are to be delivered over a long period of time.

To address this concern, in some embodiments of the present technology,the depot 100 may comprise multiple therapeutic regions 200 separated byone or more control regions 300 (for example, as shown in FIGS. 6-8).Such a configuration allows the therapeutic agent in each therapeuticregion 200 (which carries a fraction of the total payload), to beindividually sequestered. In the event a particular control region iscompromised, only the fractional payload corresponding to thetherapeutic region associated with the compromised control region wouldprematurely release. For example, in some of the foregoing embodiments,the total payload of the depot 100 may be at least 100 mg, at least 150mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg,at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, orat least 1000 mg of therapeutic agent, such as an analgesic (e.g.,bupivacaine, ropivacaine, etc.). Likewise, in some embodiments thefractional payload of each therapeutic region or sub-region may be up to1%, up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, upto 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to100% of the total payload contained within the depot 100. As a result,if any single sub-region 202 of the therapeutic region 200 iscompromised, it can release only a proportionate fraction of the totalpayload of the depot.

In some embodiments, each of the therapeutic regions and each of thecontrol regions is a micro-thin layer. In some embodiments, the depotcomprises from about 2 to about 100 therapeutic regions, or from about 2to about 50 therapeutic regions, or from about 2 to about 10 therapeuticregions.

FIGS. 9A-11 show some aspects of the present technology in which thedepots 100 may have one or more therapeutic regions 200 completelyenclosed or surrounded by one or more control regions 300. In contrastto the previously described embodiments, at least one therapeutic regionof such fully-enclosed embodiments does not have any exposed surfacearea. For example, as shown in FIGS. 9A and 9B, in some embodiments thedepot 100 may comprise a therapeutic region 200 surrounded orfully-enclosed by a control region 300 such that no portion of thetherapeutic region 200 is exposed through the control region 300. As aresult, the control region 300 substantially prevents contact betweenthe therapeutic agent and physiologic fluids, thereby preventing anuncontrolled, burst release of the therapeutic agent when implanted.Over time, the releasing agent imbedded in the polymer of the controlregion contacts physiologic fluids and dissolves, thereby formingmicro-diffusion openings in the control region. The combination of therestriction imposed by the control region and the micro-diffusionopenings formed by dissolution of the releasing agent enables acontrolled, linear release of the therapeutic agent from the depot overthe course of several days, weeks, or months. Although the depot 100 isshown as a rectangular, thin film in FIGS. 9A and 9B, in otherembodiments the depot 100 may have other shapes, sizes, or forms.

FIG. 10 illustrates a depot 100 having a therapeutic regionfully-enclosed by a control region 300 having a first control region 300a and a second control region 300 b. As depicted in FIG. 10, in someembodiments the therapeutic region 200 may be sandwiched between thefirst control region 300 a and the second control region 300 b, and thefirst and second control regions 300 a-b may be bonded via heatcompression around the therapeutic region 200 to enclose the therapeuticregion 200 therebetween. In certain embodiments, a bioresorbable polymermay be wrapped around the entire depot and sealed on the top or bottomsurface creating a control region structure similar to that depicted inFIG. 9A. The outer portion of the first and second control regions 300a-b may be incorporated as the final wrapped layer to seal the edges.Additionally, the first and second control regions 300 a-b can beintegrally formed with each other using dip coating and/or spray coatingtechniques, such as dipping the therapeutic region 200 in a solution ofthe control region material or spraying a solution of control regionmaterial onto the surfaces of the therapeutic region 200.

In FIG. 10, the first control region 300 a can have first and secondsub-regions 302 a-b, and the second control region 300 b can have firstand second sub-regions 302 c-d. The first control region 300 a candefine a top control region member, and the first and second sub-regions302 a-b can comprise a first top control layer and a second top controllayer, respectively. The second control region 300 b can define a bottomcontrol region member, and the first and second sub-regions 302 c-d cancomprise a first bottom control layer and a second bottom control layer,respectively. The first and second top/bottom control layers can be anyvariation of the first and second control sub-regions discussed abovewith reference to FIG. 5. In addition, the first top control layer ofthe top control region member may have the same or different properties(e.g., thickness, polymer, releasing agent, concentration of releasingagent, total amount of releasing agent, polymer to releasing agentratio, etc.) as the first bottom control layer of the bottom controlregion member. Similarly, the second top control layer of the topcontrol region member may have the same or different properties as thesecond bottom control layer of the bottom control region member.Variations in the loading and construction of the layers may be designedinto the depot 100 to achieve a release profile or kinetics that suitsthe objectives of the intended therapy. In other embodiments, the firstcontrol region 300 a and/or the second control region 300 b has a singlelayer.

FIG. 11 shows some embodiments in which the depot 100 may have atherapeutic region 200 fully-enclosed by a control region 300 havingdifferent sub-region configurations. The depot 100 of FIG. 11 includes afirst control region 300 a and a second control region 300 b thattogether fully enclose the therapeutic region 200. In contrast to thedepot 100 shown in FIG. 10, the first control region 300 a has an outertop control region 301 a with first and second top sub-control regions302 a and 302 b, respectively, and an inner top control region 301 bwith first and second top layers 303 a and 303 b. The first and secondtop layers 303 a-b are over only the top surface of the therapeuticregion 200, while the first and second top sub-control regions 302 a-bcover a portion the sidewall of the therapeutic region 200 and the innertop control region 301 b. The second control region 300 b has an outerbottom control region 301 c with first and second bottom sub-controlregions 302 c and 302 d, respectively, and an inner bottom controlregion 301 d with first and second bottom layers 303 d and 303 e,respectively. As such, when the depot 100 is positioned at the treatmentsite in vivo, the outer top and bottom control regions 301 a and 301 care between: (a) the therapeutic region 200 and the inner top and bottomcontrol regions 301 b and 301 d, respectively, and (b) physiologicfluids at the treatment site. In certain embodiments, such as that shownin FIG. 11, one or more of the outer top/bottom control regions 301a/301 c may comprise one or more control sub-regions, and one or moreinner top/bottom control regions 301 b/301 d may include one or morecontrol sub-regions.

FIG. 12 shows a cross-section of a spherical depot 100 in accordancewith several embodiments of the present technology having a plurality ofalternating therapeutic regions 200 and control regions 300 inaccordance with the present technology. The depot 100 may have two ormore control regions 300 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.),and the depot may have one or more therapeutic regions 200 (e.g., 1, 2,3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one controlregion 300. In some embodiments, each of the therapeutic regions 200 maycomprise a single layer and/or each of the control regions 300 maycomprise a single layer. In some embodiments, one, some, or all of thetherapeutic regions 200 may comprise multiple layers and/or one, some,or all of the control regions 300 may comprise multiple layers.Moreover, one or more of the individual control regions 200 and/or oneor more of the therapeutic regions 300 may have the same or differentamounts and/or types of releasing agent, and one or more of thetherapeutic regions 200 may have the same or different amounts and/ortypes of therapeutic agent.

FIG. 13 shows a depot 100 in accordance with several embodiments of thepresent technology having a therapeutic region 200 enclosed on the topand bottom surfaces as well as two of four sides of the sidewall by acontrol region 300. This configuration is expected to release thetherapeutic agent more slowly, at least initially, compared to a depotwith the same dimensions and fully exposed sidewalls (see, e.g., thedepot 100 shown in FIG. 4).

The release kinetics of the depots of the present technology may also betuned for a particular application by varying the shape and size of thedepot 100. Depending on the therapeutic dosage needs, anatomicaltargets, etc., the depot 100 can be different sizes, shapes, and formsfor implantation and/or injection in the body by a clinicalpractitioner. The shape, size, and form of the depot 100 should beselected to allow for ease in positioning the depot at the target tissuesite, and to reduce the likelihood of, or altogether prevent, the depotfrom moving after implantation or injection. This may be especially truefor depots being positioned within a joint (such as a knee joint),wherein the depot is a flexible solid that is structurally capable ofbeing handled by a clinician during the normal course of a surgerywithout breaking into multiple pieces and/or losing its general shape.Additionally, the depot may be configured to be placed in the knee of apatient and release the analgesic in vivo for up to 7 days withoutbreaking into multiple pieces.

Some of the form factors producible from the depot 100 or to be usedadjunctive to the depot for implantation and fixation into the bodyinclude: strips, ribbons, hooks, rods, tubes, patches, corkscrew-formedribbons, partial or full rings, nails, screws, tacks, rivets, threads,tapes, woven forms, t-shaped anchors, staples, discs, pillows, balloons,braids, tapered forms, wedge forms, chisel forms, castellated forms,stent structures, suture buttresses, coil springs, sponges, capsules,coatings, matrices, wafers, sheets, strips, ribbons, pills, pellets.

The depot 100 may also be processed into a component of the form factorsmentioned in the previous paragraph. For example, the depot could berolled and incorporated into tubes, screws, tacks, or the like. In thecase of woven embodiments, the depot may be incorporated into amulti-layer woven film/braid/mesh wherein some of the filaments used arenot the inventive device. In one example, the depot is interwoven withDacron, polyethylene or the like. For the sake of clarity, any formfactor corresponding to the depot of the present technology, includingthose where only a portion or fragment of the form factor incorporatesthe depot, may be referred to herein as a “depot.”

As shown in FIGS. 14A-14H, in various embodiments, the depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film, ribbon, strip or sheet, a paste, a slab,microparticles, nanoparticles, pellets, mesh or the like. FIG. 14A showsa rectilinear depot 100. FIG. 14B shows a circular depot 100. FIG. showsa triangular depot 100. FIG. 14D show cross-like depot 100, FIG. 14Eshows a star-like depot 100, and FIG. 14F shows a toroidal depot 100.FIG. 14G shows a spheroid depot 100, and FIG. 14H shows a cylindricaldepot 100. The shape of the depot 100 can be selected according to theanatomy to fit within a given space and provide the desired fixation andflexibility properties. This is because the fit, fixation andflexibility of the depot may enhance the ease of implanting the depot,ensure delivery of the therapeutic agent to the target site, and prolongthe durability of the implant in dynamic implant sites.

In various embodiments, the depot can be different sizes, for example,the depot may be a length of from about 0.4 mm to 100 mm and have adiameter or thickness of from about 0.01 to about 5 mm. In variousembodiments, the depot may have a layer thickness of from about 0.005 to5.0 mm, such as, for example, from 0.05 to 2.0 mm. In some embodiments,the shape may be a rectangular or square sheet having a ratio of widthto thickness in the range of 20 or greater, 25 or greater, 30 orgreater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

In some embodiments, a thickness of the control region (a singlesub-control region or all sub-control regions combined) is less than orequal to 1/50, 1/75, or 1/100 of a thickness of the therapeutic region.

In some embodiments, the depot 100 has a width and a thickness, and aratio of the width to the thickness is 21 or greater. In someembodiments, the ratio is 22 or greater, 23 or greater, 24 or greater,25 or greater, 26 or greater, 27 or greater, 28 or greater, 29 orgreater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or50 or greater.

In some embodiments, the depot 100 has a surface area and a volume, anda ratio of the surface area to volume is at least 1, at least 1.5, atleast 2, at least 2.5, or at least 3.

In any of the foregoing embodiments shown and described above withrespect to FIGS. 2-14H, dissolution of the releasing agent(s) andelution of the therapeutic agent(s) can change functional mechanicalaspects of the depot 100 over time. Such mechanical aspects includestructural integrity, flexural strength, tensile strength, or othermechanical characteristics of the depot 100. In some instances,undesirable degradation of the depot 100, such as premature degradation,can cause mechanical failure of the depot 100 and a correspondingundesirable burst release of therapeutic agent into the body.Accordingly, it can be beneficial for the depot 100 to maintainsufficient flexural strength and/or mechanical integrity in vivo for atleast a predetermined period of time or until a predetermined proportionof therapeutic agent has been released from the depot 100. The depot 100can be considered to maintain its structural integrity if the depot 100remains largely intact with only partial or gradual reduction due toelution of therapeutic agent or dissolution of the control layers orreleasing agent. The depot 100 can be considered to lose its structuralintegrity if it separates (e.g., fractures) into multiple componentpieces, for example, with two or more of the resulting pieces being atleast 5% of the previous size of the depot 100. Alternatively, oradditionally, the depot 100 can be considered to lose its structuralintegrity if the release rate of the therapeutic agent increases by morethan a factor of three as compared to the release rate of therapeuticagent in a control depot submerged in a buffered solution.

In some embodiments, the depot 100 is configured to maintain itsstructural integrity in vivo for at least a predetermined length oftime. For example, the depot 100 can be configured to maintain itsstructural integrity in vivo for at least 1 day, at least 2 days, atleast 3 days, at least 4 days, at least 5 days, at least 6 days, atleast 7 days, at least 8 days, at least 9 days, at least 10 days, atleast 11 days, at least 12 days, at least 13 days, at least 14 days, atleast 15 days, at least 16 days, at least 17 days, at least 18 days, atleast 19 days, at least 20 days, at least 21 days, at least 22 days, atleast 23 days, at least 24 days, at least 25 days, at least 26 days, atleast 27 days, at least 28 days, at least 29 days, or at least 30 days,at least 40 days, at least 50 days, at least 60 days, at least 70 days,at least 90 days, at least 100 days, at least 200 days, at least 300days, or at least 365 days.

In some embodiments, the depot 100 is configured to maintain itsstructural integrity in vivo until at least a predetermined proportionof therapeutic agent payload has been released from the depot. Forexample, the depot 100 can be configured to maintain its structuralintegrity in vivo until at least 5% by weight of the original payloadhas been released, at least 10% by weight of the original payload hasbeen released, at least 15% by weight of the original payload has beenreleased, at least 20% by weight of the original payload has beenreleased, at least 25% by weight of the original payload has beenreleased, at least 30% by weight of the original payload has beenreleased, at least 35% by weight of the original payload has beenreleased, at least 40% by weight of the original payload has beenreleased, at least 45% by weight of the original payload has beenreleased, at least 50% by weight of the original payload has beenreleased, at least 55% by weight of the original payload has beenreleased, at least 60% by weight of the original payload has beenreleased, at least 65% by weight of the original payload has beenreleased, at least 70% by weight of the original payload has beenreleased, at least 75% by weight of the original payload has beenreleased, at least 80% by weight of the original payload has beenreleased, at least 85% by weight of the original payload has beenreleased, at least 90% by weight of the original payload has beenreleased, or until at least 95% by weight of the original payload hasbeen released.

One aspect of the structural integrity of the depot 100 when it is invivo can be quantified using a bend test, such as a three-point bendtest that measures flexural properties including the flexural strengthand/or maximum flexural stress sustained by a specimen before breaking.Such a bend test may represent (e.g., simulate) the forces that thedepot 100 will encounter in vivo in an anatomical joint (e.g., a kneejoint). In one example, a depot can be subjected to a three-point bendtest based on ASTM-D790-17, “Standard Test Methods for FlexuralProperties of Unreinforced and Reinforced Plastics and ElectricalInsulating Materials.” The text of this standard is hereby incorporatedby reference in its entirety. The depot 100 may be suspended in a mediumconfigured to simulate in vivo conditions, for example a phosphatebuffered saline (PBS) at approximately 37° C. The bend test may beperformed after different time periods of submersion in the medium toevaluate changes in the flexural strength of the depot 100 over time insimulated in vivo conditions.

Table 1 shows the maximum flexural load sustained by four differentsamples of the depot 100 at different time periods following submersionin the medium as measured using a three-point bend test with maximumdeflection set at 2.13 mm. The values in Table 1 reflect measurementsmade from two instances of each of the listed samples. FIG. 15 is agraph illustrating these values plotted graphically and fitted withtrendlines. In each of these four samples, the depot 100 includes atherapeutic region 200 surrounded by upper and lower control regions 300a-b as shown and described above with reference to FIG. 4 or 5. Thetherapeutic region 200 has exposed lateral edges 202 between the firstand second control regions 300 a-b. The depots 100 each have lateraldimensions of approximately 2.5 cm by 1.5 cm, with a thickness ofapproximately 1 mm.

Sample 1 is a depot having a therapeutic region with a ratio by weightof releasing agent to polymer to therapeutic agent of 0.5:10:20. Thepolymer in this sample is P(DL)GACL with a PDLLA:PGA:PCL ratio of 6:3:1,the releasing agent is Tween 20, and the therapeutic agent isbupivacaine hydrochloride. In this sample, the depot includes a firstcontrol region 300 a comprising a single control layer over the uppersurface of the therapeutic region 200 and a second control region 300 bcomprising single control layer over the lower surface of thetherapeutic region 200, as shown and described above with reference toFIG. 4. Each control region 300 a-b individually has a ratio ofreleasing agent to polymer of 5:10.

Sample 2 is a depot having a therapeutic region 200 with a ratio byweight of releasing agent to polymer to therapeutic agent of 1:10:20.The polymer in this sample is PLGA with a PLA:PGA ratio of 1:1, thereleasing agent is Tween 20, and the therapeutic agent is bupivacainehydrochloride. Similar to Sample 1, the depot of Sample 2 includes acontrol region 300 comprising a first control region 300 a with a singlecontrol layer over the upper surface of the therapeutic region 200 and asecond control region 300 b comprising a single control layer over thelower surface of the therapeutic region 200, as shown and describedabove with reference to FIG. 4. Each control region 300 a-b individuallyhas a ratio of releasing agent to polymer of 5:10.

Sample 3 is a depot having therapeutic region 200 with a ratio by weightof releasing agent to polymer to therapeutic agent of 5:10:20. Thepolymer in this sample is P(DL)GACL with a PDLLA:PGA:PCL ratio of 6:3:1,the releasing agent is Tween 20, and the therapeutic agent isbupivacaine hydrochloride. In this sample, the depot includes a controlregion 300 comprising a first control region 300 a with two sub-controlregions 302 a-b over the upper surface of the therapeutic region 200,and a second control region 300 b with two sub-control regions 302 c-d,as shown and described above with reference to FIG. 5. Each of the innersub-control regions 302 b and 302 c contacts the surface of thetherapeutic region 200 and has a ratio of releasing agent to polymer of5:10, and each of the outer sub-control regions 302 a and 302 d has aratio of releasing agent to polymer of 1:10. The depot of Sample 3,therefore, includes a total of four sub-control regions.

Sample 4 is a depot having a therapeutic region 200 with a ratio byweight of releasing agent to polymer to therapeutic agent of 5:10:20.The polymer in this sample is PLGA with a PLA:PGA ratio of 1:1, thereleasing agent is Tween 20, and the therapeutic agent is bupivacainehydrochloride. As with Sample 3, the depot of Sample 4 includes acontrol region 300 having first and second control region 300 a-b thateach have two sub-control regions 302 a-b and 302 c-d, respectively, asshown and described with respect to FIG. 5. The depot of Sample 4according also has a total of four sub-control regions 302 a-d, two overthe upper surface of the therapeutic region 200 and two over the lowersurface of the therapeutic region 200. The inner of the sub-controlregions 302 b and 302 c has a ratio of releasing agent to polymer of5:10, and the outer of the sub-control regions 302 a and 302 d has aratio of releasing agent to polymer of 1:10.

TABLE 1 Depot Sample Day 0 Day 1 Day 3 Day 7 Day 14 Day 28 Sample 1: Nobreak 5.553 N 2.903 N 0.569 N 1.263 N Not tested P(DL)GACL 6:3:1 1.25lbf 0.0653 lbf 0.134 lbf 0.284 lbf 2 control layers Sample 2: 5.623 N5.447 N 4.623 N 1.386 N Not tested Not tested PLGA 1:1 1.264 lbf 1.22lbf 1.04 lbf 0.312 lbf 2 control layers Sample 3: No break 5.474 N Nottested 2.430 N 0.605 N Sample P(DL)GACL 6:3:1 1.23 lbf 0.546 lbf 0.136lbf degraded 4 control layers Sample 4: No break 6.763 N Not tested1.816 N 0.869 N Sample PLGA 1:1 1.52 lbf 0.408 lbf 0.195 lbf degraded 4control layers

As shown in Table 1, all samples were intact and maintained sufficientstructural integrity after 14 days of being suspended in the medium towithstand a bending force before fracturing. Although the maximum loadtolerated by each sample decreased over time, the flexural strength ofthese samples at 14 days was sufficient to maintain the structuralintegrity desired for implantation in an active joint, such as the kneeor shoulder. As shown above, for two of the samples tested at 28 days,the samples had degraded such that the test could not be performedbecause the sample was no longer structurally intact. In such instances,it may be desirable to configure the depots such that all orsubstantially all the therapeutic agent payload has been released fromthe depot prior to its degradation and loss of structural integrity.

In this series of experiments summarized in Table 1, the sample depotsare generally flexible at Day 0 before submersion in PBS. Followingsubmersion, the flexural strength of the depots decreased such that thedepots became more brittle with time. Yet, at 7-14 days, the depots werestill sufficiently functionally intact. Without being bound by theory,it is believed that after the therapeutic agent has eluted, the depotsgradually become an empty polymer matrix. For example, after 14-28 daysin the solution, the depots may weigh only approximately 30% of theirstarting weight before submersion in the PBS. At this lower weight andin the porous state, the depots may be more brittle, with lower flexuralstrength and less resistance to bending loads.

As noted above, it can be advantageous for the depots 100 to maintaintheir structural integrity and flexural strength even while theygradually degrade as the therapeutic agent payload releases into thebody. In some embodiments, the depot 100 can be configured such that, inin vitro testing utilizing a three-point bend test, the flexuralstrength of the depot 100 decreases by no more than 95%, no more than90%, no more than 85%, no more than 80%, no more than 75%, no more than70%, no more than 65%, no more than 60%, no more than 55%, no more than50%, no more than 45%, no more than 40%, no more than 35%, no more than30%, no more than 25%, no more than 20%, no more than 15%, no more than10%, or no more than 5% after being submerged in PBS for a predeterminedperiod of time. In various embodiments, the predetermined period of timethat the depot 100 is submerged in PBS before being subjected to thethree-point bend test is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15days, 16 days, 17 days, 18 days, 19 days, 20 days, after 21 days, after22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more.In at least some embodiments, the change in flexural strength of thedepot 100 can be measured between day 0 (e.g., before submersion in thePBS) and a subsequent time after some period of submersion in PBS. Inother embodiments, the change in flexural strength of the depot 100 canbe measured between day 1 (e.g., after 24 hours of submersion in PBS)and a subsequent time following longer submersion in PBS.

In some embodiments, the depot 100 can be configured such that, in invitro testing utilizing a three-point bend test, the flexural strengthof the depot 100 decreases by no more than 95%, no more than 90%, nomore than 85%, no more than 80%, no more than 75%, no more than 70%, nomore than 65%, no more than 60%, no more than 55%, no more than 50%, nomore than 45%, no more than 40%, no more than 35%, no more than 30%, nomore than 25%, no more than 20%, no more than 15%, no more than 10%, orno more than 5% over the time period in which a predetermined percentageof the initial therapeutic agent payload is released while the depot 100is submerged in PBS. In various embodiments, the predeterminedpercentage of payload released when the depot 100 is submerged in PBSbefore being subjected to the three-point bend test is about 5%, about10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about t 85%, about 90%, or about 95%. As noted above, inat least some embodiments, the change in flexural strength of the depot100 can be measured between day 0 (prior to submersion in PBS) or day 1(after 24 hours of submersion in PBS) and a subsequent following longersubmersion in PBS.

In some embodiments, the depot 100 has (a) lateral dimensions of about1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a payload oftherapeutic agent sufficient to release about 100 mg to about 500 mg oftherapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 days, and the depot 100 is configured to remainsufficiently mechanically intact to provide sustained, controlledrelease of therapeutic agent for at least 7 days. Such embodiments ofthe depot 100 can comprise the therapeutic region 200 with a therapeuticagent and the control region 300. The control region 300 can have firstand second control regions 300 a-b, such as those shown and describedabove with reference to FIGS. 4-13, and the control region 300 comprisesa bioresorbable polymer and a releasing agent mixed with thebioresorbable polymer. The releasing agent is configured to dissolvewhen the depot 100 is placed in vivo to form diffusion openings in thecontrol region 300. The depot 100 is further configured such that,following submersion of the depot 100 in a buffer solution for sevendays, the flexural strength of the depot 100 decreases by no more than75%, or by no more than 70%, or by no more than 65%, or by no more than60%, or by no more than 55%, or by no more than 50%, or by no more than45%

In some embodiments, the depot 100 has (a) lateral dimensions of about1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a payload oftherapeutic agent sufficient to release about 100 mg to about 500 mg oftherapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 days, and the depot 100 is configured to remainsufficiently mechanically intact to provide sustained, controlledrelease of therapeutic agent for at least 7 days. Such embodiments ofthe depot 100 can comprise the therapeutic region 200 with a therapeuticagent and the control region 300. The control region 300 can have firstand second control regions 300 a-b, such as those shown and describedabove with reference to FIGS. 4-13, and the control region 300 comprisesa bioresorbable polymer and a releasing agent mixed with thebioresorbable polymer. The releasing agent is configured to dissolvewhen the depot 100 is placed in vivo to form diffusion openings in thecontrol region 300. The depot is further configured such that, followingsubmersion of the depot in buffer solution until approximately 75% ofthe therapeutic agent by weight has been released, the flexural strengthof the depot decreases by no more than 75%, or by no more than 70%, orby no more than 65%, or by no more than 60%, or by no more than 55%, orby no more than 50%, or by no more than 45%.

A. Therapeutic Region

The total payload and release kinetics of the depots 100 of the presenttechnology may be tuned for a particular application by varying thecomposition of the therapeutic region 200. In many embodiments, thetherapeutic region 200 may include a high therapeutic payload of thetherapeutic agent, especially as compared to other known polymer devicesof equal thickness or polymer weight percentage. In some embodiments,the ratio of releasing agent to polymer to therapeutic agent in thetherapeutic region 200 is of from about 0.1:10:20 to about 2:10:20, andin some embodiments of from about 0.1:10:20 to about 1:10:20, and insome embodiments of from about 0.1:10:20 to about 0.5:10:20, and in someembodiments of from about 0.5:10:20 to about 0.1:10:20

In some embodiments the therapeutic region 200 (or one or moretherapeutic sub-regions) comprises the therapeutic agent as anessentially pure compound or formulated with a pharmaceuticallyacceptable carrier such as diluents, adjuvants, excipients or vehiclesknown to one skilled in the art. In some embodiments, the therapeuticregion 200 may comprise a single layer, and in some embodiments thetherapeutic region may include a plurality of microlayers containing thetherapeutic agent in the same and/or different amounts. In someembodiments, the therapeutic region 200 may comprise one or moresub-regions containing the therapeutic agent and a polymer and/orreleasing agent, and (b) one or more sub-regions containing thetherapeutic agent as an essentially pure compound (i.e., without anypolymer and/or releasing agent). In some embodiments, the therapeuticregion 200 includes releasing agent, and in some embodiments, thetherapeutic region 200 does not include any releasing agent prior toimplantation of the depot 100 at the treatment site.

In some aspects of the technology, the therapeutic region 200 maycomprise a microlayer structure of multiple micro-thin sheets ofbiodegradable, bioresorbable polymer, each micro-thin sheet (or layer)loaded with therapeutic agent. In this microlayer embodiment of thetherapeutic region 200, the micro-thin sheets may have a substantiallyuniform construction and are stacked and bonded together. Thesemicro-thin polymer sheets may each have a thickness from approximately 5μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm,or 7 to 9 μm thick, with the overall thickness of the therapeutic regionbased on the total number of micro-thin sheets that are stacked. Havinga therapeutic region 200 with multiple layers may provide a more linear,controlled release of the therapeutic agent over time (beyond the firstday of implantation). In addition, layering of the therapeutic regionmay also contribute to a more flexible, structurally competent depot (ascompared to a depot having a therapeutic region comprised of puretherapeutic agent). Such durability is beneficial for the clinician whenhandling/manipulating the depot before and while positioning the depot100 at a treatment site.

B. Control Region

The composition of the control region 300 may also be varied. Forexample, in many embodiments, the control region 300 does not includeany therapeutic agent at least prior to implantation of the depot at thetreatment site. In some embodiments, the control region 300 may includea therapeutic agent which may be the same as or different than thetherapeutic agent in the therapeutic region 200.

Within the control region 300, the amount of releasing agent may bevaried to achieve a faster or slower release of the therapeutic agent.In those embodiments where both the therapeutic region 200 and controlregion 300 include a releasing agent, the type of releasing agent withinthe therapeutic region 200 may be the same or different as the releasingagent in the control region 300. In some embodiments, a concentration ofa first releasing agent within the control region is the greater than aconcentration of a second releasing agent (the same or different as thefirst releasing agent) within the therapeutic region. In someembodiments, a concentration of the releasing agent within the controlregion is the less than a concentration of the releasing agent withinthe therapeutic region. In some embodiments, a concentration of thereleasing agent within the control region 300 is the same as aconcentration of the releasing agent within the therapeutic region 200.

As previously mentioned, in some embodiments the depot 100 may include acontrol region 300 comprised of multiple layers. In some embodiments,one, some, or all of the layers within the control region comprise amicro-thin sheet. Without being bound by theory, it is believed thatsuch a multilayer configuration improves the control region's ability tocontrol the release of the therapeutic agent (as compared to a singlelayer control region). As shown, the channels left by dissolution of thereleasing agent in both microlayers of the control region create a pathfor a released therapeutic agent to travel that is longer and,potentially, more cumbersome to traverse as compared to the more directpath created by the channels in the single layer control region. Themultiple micro-thin sheets of the control region in this embodiment maybe heat compressed together on the therapeutic region 200 to regulatethe therapeutic agent release rate by allowing a releasing agent to formindependent non-contiguous channels through each control region from thein vivo environment to the therapeutic region. Having a control region300 with multiple layers may provide a more linear, controlled releaseof the therapeutic agent over time (beyond the first day ofimplantation). In addition, layering of the control region 300 may alsocontribute to a more flexible, structurally competent depot (as comparedto a depot having a therapeutic region comprised of pure therapeuticagent). Such durability is beneficial for the clinician whenhandling/manipulating the depot 100 before and while positioning thedepot 100 at a treatment site.

In various embodiments of the depots disclosed herein, the controlregion may take several different forms. In some embodiments (forexample, FIG. 4), the control region may comprise a single layer oneither side of the therapeutic region 200 comprised of biodegradable,bioresorbable polymer mixed with a releasing agent. In some embodiments,the control region itself may comprise a structure having multiplelayers of biodegradable, bioresorbable polymer. The layers of thismultiple layer structure may additionally or alternatively comprisemultiple micro-thin sheets or layers (i.e., microlayers), where eachmicro-thin layer has a thickness of from approximately 5 μm to 100 μm, 5μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, or 7 μm to 9μm. In these multi-layered embodiments of the control region 300, atleast one layer of the multilayer structure may comprise a polymer mixedwith a releasing agent and at least one other layer of the multilayerstructure may comprise a polymer having no releasing agent mixedtherein. In some embodiments, the control region 300 may comprise amultilayer structure wherein multiple layers have a releasing agentmixed into each polymer layer, but these layers may have the releasingagent in different concentrations. In particular embodiments, themultiple control layers have a releasing agent mixed into each polymerlayer, and at least one of the layers may have a different releasingagent than at least one of the other layers.

C. Therapeutic Agents

The therapeutic agent carried by the depots 100 of the presenttechnology may be any biologically active substance (or combination ofsubstances) that provides a therapeutic effect in a patient in needthereof. As used herein, “therapeutic agent” or “drug” may refer to asingle therapeutic agent, or may refer to a combination of therapeuticagents. In some embodiments, the therapeutic agent may include only asingle therapeutic agent, and in some embodiments, the therapeutic agentmay include two or more therapeutic agents for simultaneous orsequential release.

In several embodiments, the therapeutic agent includes an analgesicagent. The term “analgesic agent” or “analgesic” includes one or morelocal or systemic anesthetic agents that are administered to reduce,prevent, alleviate or remove pain entirely. The analgesic agent maycomprise a systemic and/or local anesthetic, narcotics, and/oranti-inflammatory agents. The analgesic agent may comprise thepharmacologically active drug or a pharmaceutically acceptable saltthereof. Suitable local anesthetics include, but are not limited to,bupivacaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine,trimecaine, carticaine, articaine, lidocaine, prilocaine, benzocaine,procaine, tetracaine, chloroprocaine, and combinations thereof.Preferred local anesthetics include bupivacaine, lidocaine andropivacaine. Typically, local anesthetics produce anesthesia byinhibiting excitation of nerve endings or by blocking conduction inperipheral nerves. Such inhibition is achieved by anesthetics reversiblybinding to and inactivating sodium channels. Sodium influx through thesechannels is necessary for the depolarization of nerve cell membranes andsubsequent propagation of impulses along the course of the nerve. When anerve loses depolarization and capacity to propagate an impulse, theindividual loses sensation in the area supplied by the nerve. Anychemical compound possessing such anesthetic properties is suitable foruse in the present technology.

In some embodiments, the therapeutic agent includes narcotics, forexample, cocaine, and anti-inflammatory agents. Examples of appropriateanti-inflammatory agents include steroids, such as prednisone,betamethasone, cortisone, dexamethasone, hydrocortisone andmethylprednisolone. Other appropriate anti-inflammatory agents includenon-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin,Ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol,celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac,diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac,fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, andother COX-2 inhibitors, and combinations thereof.

In some embodiments, the therapeutic agent comprises an antibiotic, anantimicrobial or antifungal agent or combinations thereof. For example,suitable antibiotics and antimicrobials include, but are not limited to,amoxicillin, amoxicillin/clavulanate, cephalexin, ciprofloxacin,clindamycin, metronidazole, azithromycin, levofloxacin,sulfamethoxazole/trimethoprim, tetracycline(s), minocycline,tigecycline, doxycycline, rifampin, triclosan, chlorhexidine,penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin,gentamycin, cephalosporin(s), carbapenems, imipenem, ertapenem,antimicrobial peptides, cecropin-mellitin, magainin, dermaseptin,cathelicidin, α-defensins, and α-protegrins. Antifungal agents include,but are not limited to, ketoconazole, clortrimazole, miconazole,econazole, intraconazole, fluconazole, bifoconazole, terconazole,butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole,voriconazole, terbinafine, amorolfine, naftifine, griseofulvin,haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox,flucytosine, terbinafine, and amphotericin B.

In several embodiments, the therapeutic agent may be anadrenocorticostatic, a β-adrenolytic, an androgen or antiandrogen, anantianemic, a antiparasitic, an anabolic, an anesthetic or analgesic, ananaleptic, an antiallergic, an antiarrhythmic, an anti-arteriosclerotic,an antibiotic, an antidiabetic, an antifibrinolytic, an anticonvulsive,an angiogenesis inhibitor, an anticholinergic, an enzyme, a coenzyme ora corresponding inhibitor, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antimycotic, an antiseptic, ananti-infective, an antihemorrhagic, a β-receptor antagonist, a calciumchannel antagonist, an antimyasthenic, an antiphlogistic, anantipyretic, an antirheumatic, a cardiotonic, a chemotherapeutic, acoronary dilator, a cytostatic, a glucocorticoid, a hemostatic, animmunoglobulin or its fragment, a chemokine, a cytokine, a mitogen, acell differentiation factor, a cytotoxic agent, a hormone, animmunosuppressant, an immunostimulant, a morphine antagonist, an musclerelaxant, a narcotic, a vector, a peptide, a (para)sympathicomimetic, a(para)sympatholytic, a protein, a cell, a selective estrogen receptormodulator (SERM), a sedating agent, an antispasmodic, a substance thatinhibits the resorption of bone, a vasoconstrictor or vasodilator, avirustatic or a wound-healing agent.

In various embodiments, the therapeutic agent comprises a drug used inthe treatment of cancer or a pharmaceutically acceptable salt thereof.Such chemotherapeutic agents include antibodies, alkylating agents,angiogenesis inhibitors, antimetabolites, DNA cleavers, DNAcrosslinkers, DNA intercalators, DNA minor groove binders, enediynes,heat shock protein 90 inhibitors, histone deacetylase inhibitors,immunomodulators, microtubule stabilizers, nucleoside (purine orpyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors,topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, andserine/threonine kinase inhibitors. Specific therapeutic agents include,but are not limited to, adalimumab, ansamitocin P3, auristatin,bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib,busulfan, callistatin A, camptothecin, capecitabine, carboplatin,carmustine, cetuximab, cisplatin, cladribin, cytarabin, cryptophycins,dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin,duocarmycin, dynemycin A, epothilones, etoposide, floxuridine,fludarabine, 5-fluorouracil, gefitinib, gemcitabine, ipilimumab,hydroxyurea, imatinib, infliximab, interferons, interleukins,beta-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine,melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib,oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid(SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab,trichostatin A, vinblastine, vincristine, vindesine, and tamoxifen.

In some embodiments, the therapeutic agent comprises a botulinum toxin(or neurotoxin) drug used in the treatment of various neuromuscularand/or neuroglandular disorders and neuropathies associated with pain.The botulinum toxin (or neurotoxin) may comprise the pharmacologicallyactive drug or a pharmaceutically acceptable salt thereof. The botulinumtoxin (or neurotoxin) as described and used herein may be selected froma variety of strains of Clostridium botulinum and may comprise thepharmacologically active drug or a pharmaceutically acceptable saltthereof. In one embodiment, the botulinum toxin is selected from thegroup consisting of botulinum toxin types A, B, C, D, E, F and G. In apreferred embodiment, the botulinum toxin is botulinum toxin type A.Commercially available botulinum toxin, BOTOX® (Allergan, Inc., Irvine,Calif.), consists of a freeze-dried, purified botulinum toxin type Acomplex, albumin and sodium chloride packaged in sterile, vacuum-driedform.

The paralytic effect of botulinum toxin is the most common benefit ofcommercial therapeutics, where muscles are relaxed in order to treatmuscle dystonias, wrinkles and the like. However, it has been shown thatin addition to its anti-cholinergic effects on muscle and smooth muscle,the neurotoxin can have therapeutic effects on other non-muscular celltypes, and on inflammation itself. For example, it has been shown thatcholinergic goblet cells, which produce mucus throughout the airwaysystem, react to and can be shut down by introduction of botulinumtoxin. Research also shows that botulinum toxin has directanti-inflammatory capabilities. All of these therapeutic effects,muscle, smooth muscle, goblet cell and anti-inflammatory affects, may bederived from delivery of the toxin from the inventive devices.

A pharmaceutically acceptable salt refers to those salts that retain thebiological effectiveness and properties of neutral therapeutic agentsand that are not otherwise unacceptable for pharmaceutical use.Pharmaceutically acceptable salts include salts of acidic or basicgroups, which groups may be present in the therapeutic agents. Thetherapeutic agents used in the present technology that are basic innature are capable of forming a wide variety of salts with variousinorganic and organic acids. Pharmaceutically acceptable acid additionsalts of basic therapeutic agents used in the present technology arethose that form non-toxic acid addition salts, i.e., salts comprisingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate,tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The therapeuticagents of the present technology that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Suitable base salts are formed from baseswhich form non-toxic salts and examples are the aluminum, calcium,lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

A pharmaceutically acceptable salt may involve the inclusion of anothermolecule such as water or another biologically compatible solvent (asolvate), an acetate ion, a succinate ion or other counterion. Thecounterion may be any organic or inorganic moiety that stabilizes thecharge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counter ions. Hence, apharmaceutically acceptable salt can have one or more charged atomsand/or one or more counterion.

The therapeutic agent or pharmaceutically acceptable salt thereof may bean essentially pure compound or be formulated with a pharmaceuticallyacceptable carrier such as diluents, adjuvants, excipients or vehiclesknown to one skilled in the art. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulations and not deleterious to the recipient thereof. For example,diluents include lactose, dextrose, sucrose, mannitol, sorbitol,cellulose, glycine and the like. For examples of other pharmaceuticallyacceptable carriers, see Remington: THE SCIENCE AND PRACTICE OF PHARMACY(21st Edition, University of the Sciences in Philadelphia, 2005).

The therapeutic agent or pharmaceutically acceptable salt form may bejet milled or otherwise passed through a sieve to form consistentparticle sizes further enabling the regulated and controlled release ofthe therapeutic agent. This process may be particularly helpful forhighly insoluble therapeutic agents.

In one embodiment, the biodegradable, bioresorbable polymer used invarious layers of the depot may manifest as a layer of electrospunmicrofibers or nanofibers. Biocompatible electrospunmicrofibers/nanofibers are known in the art and may be used, forexample, to manufacture implantable supports for the formation ofreplacement organs in vivo (U.S. Patent Publication No. 2014/0272225;Johnson; Nanofiber Solutions, LLC), for musculoskeletal and skin tissueengineering (R. Vasita and D. S. Katti, Int. J. Nanomedicine, 2006, 1:1,15-30), for dermal or oral applications (PCT Publication No.2015/189212; Hansen; Dermtreat APS) or for management of postoperativepain (U.S. Patent Publication No. 2013/0071463; Palasis et al.). As amanufacturing technique, electrospinning offers the opportunity forcontrol over the thickness and the composition of the nano- ormicro-fibers along with control of the porosity of the fiber meshes(Vasita and Katti, 2006). These electrospun scaffolds arethree-dimensional and thus provide ideal supports for the culture ofcells in vivo for tissue formation. Typically, these scaffolds have aporosity of 70-90% (U.S. Pat. No. 9,737,632; Johnson; NanofiberSolutions, LLC). Suitable biodegradable polymers and copolymers for themanufacture of electrospun microfibers include, but are not limited to,natural materials such as collagen, gelatin, elastin, chitosan, silkfibrion, and hyaluronic acid, as well as synthetic materials such aspoly(ε-caprolactone) (PCL), poly(glycolic acid) (PGA),poly(lactic-co-glycolic acid) (PLGA), poly(l-lactide-co-ε-caprolactone),and poly(lactic acid) (PLA).

Electrospun microfibers that are made from a bioresorbable polymer orcopolymer and have been used in conjunction with a therapeutic agent areknown in the art. For example, Johnson et al. have disclosed thetreatment of joint inflammation and other conditions with an injectionof biocompatible polymeric electrospun fiber fragments along with acarrier medium containing chitosan (U.S. Published Application No.2016/0325015; Nanofiber Solutions, LLC). Weldon et al. reported the useof electrospun bupivacaine-eluting sutures manufactured frompoly(lactic-co-glycolic acid) in a rat skin wound model, wherein thesutures provided local anesthesia at an incision site (J. ControlRelease, 2012, 161:3, 903-909). Similarly, Palasis et al. disclosed thetreatment of postoperative pain by implanting electrospun fibers loadedwith an opioid, anesthetic or a non-opioid analgesic within a surgicalsite (U.S. Patent Publication No. 2013/0071463; Palasis et al.).Electrospun microfibers suitable for use in the present technology maybe obtained by the methods disclosed in the above cited references,which are herein incorporated in their entirety.

An important criterion for determining the amount of therapeutic agentneeded for the treatment of a particular medical condition is therelease rate of the drug from the depot of the present technology. Therelease rate is controlled by a variety of factors, including, but notlimited to, the rate that the releasing agent dissolves in vivo into thesurrounding fluid, the in vivo degradation rate of the bioresorbablepolymer or copolymer utilized. For example, the rate of release may becontrolled by the use of multiple control regions between thetherapeutic region and the physiological fluid. See, for example, FIGS.6-8.

Suitable dosage ranges utilizing the depot of the present technology aredependent on the potency of the particular therapeutic agent, but aregenerally about 0.001 mg to about 500 mg of drug per kilogram bodyweight, for example from about 0.1 mg to about 200 mg of drug perkilogram body weight, and about 1 to about 100 mg/kg-body wt. per day.Dosage ranges may be readily determined by methods known to one skilledin the art. Dosage unit forms will generally contain between about 1 mgto about 500 mg of active ingredient. For example, commerciallyavailable bupivacaine hydrochloride, marketed under the brand nameMarcaine™ (Pfizer; New York, N.Y.), is generally administered as aperipheral nerve block using a dosage range of 37.5-75 mg in a 0.25%concentration and 25 mg up to the daily maximum level (up to 400 mg) ina 0.5% concentration (Marcaine®™ package insert; FDA Reference ID:3079122). In addition, commercially available ropivacaine hydrochloride,marketed under the brand name Naropin® (Fresenius Kabi USA, LLC; LakeZurich, Ill.), is administered in doses of 5-300 mg for minor and majornerve blocks (Naropin® package insert; Reference ID: 451112G). Suitabledosage ranges for the depot of the present technology are equivalent tothe commercially available agents customarily administered by injection.

In some embodiments, the therapeutic region 200 includes at least 15% byweight of the analgesic, at least 20% by weight of the analgesic, atleast 30% by weight of the analgesic, at least 40% by weight of theanalgesic, at least 50% by weight of the analgesic, at least 60% byweight of the analgesic, at least 70% by weight of the analgesic, atleast 80% by weight of the analgesic, at least 90% by weight of theanalgesic, or 100% by weight of the analgesic.

In some embodiments, the depot includes at least 15% by weight of theanalgesic, at least 20% by weight of the analgesic, at least 30% byweight of the analgesic, at least 40% by weight of the analgesic, atleast 50% by weight of the analgesic, at least 60% by weight of theanalgesic, at least 70% by weight of the analgesic, at least 80% byweight of the analgesic, at least 90% by weight of the analgesic, or100% by weight of the analgesic. In many embodiments, the depot 100includes at least 50% by weight of the analgesic.

In some aspects of the technology, the therapeutic region 200 mayinclude multiple layers. In such embodiments, the multiple layers mayimprove efficient loading of therapeutic agents. For example,multilayering may be a direct and effective way of loading substantialamounts of therapeutic agent. It can often be challenging to load alarge amount of therapeutic agent in a single film layer, even byincreasing the drug to polymer ratio or increasing the thickness of thelayer. Even when the thickness of the therapeutic region can betheoretically increased to load more drug, consistent fabrication of athick therapeutic region via casting could prove to be a challenge. Incontrast, the stacking and bonding of thin films or sheets, each with apredetermined load of therapeutic agent, may present as a more reliablecasting alternative. Data from an example of loading an analgesic (i.e.,ropivacaine) is provided in Table 2.

TABLE 2 Drug load (ug) Thickness (mm) Single layer 212.66 0.019 Fivelayers 1120.83 0.046 Multiple 5.27 2.42

As but one example, a single layer loaded with ropivacaine and having athickness of 0.019 mm was produced. A 5-layer film sample, where eachlayer was loaded with ropivacaine, having a thickness of 0.046 mm wasalso produced. Even though the thickness of the 5-layer film sample wasonly 2.42 times the thickness of the single layer, the load oftherapeutic agent in the 5-layer sample was 5.27 times that of thesingle layer sample. Accordingly, the multilayering approach enabled asubstantially higher density of therapeutic agent.

As described above, heat compression bonding of multiple layers enablesan effective reduction in film thickness and an increased density oftherapeutic agent loading. In the example illustrated in Table 2, themultilayer structure enabled a 124% increase in the density of thetherapeutic agent. In other embodiments, the increase in density of thetherapeutic agent enabled by a multilayer structure of the therapeuticregion may be approximately 50%, 75%, 100%, 125%, 150% or 200%.

D. Biodegradable Polymers

The depots 100 of the present technology are comprised of bioresorbablepolymers. In some embodiments, both the therapeutic region 200 and thecontrol region 300 comprise a polymer (or mix of polymers), which can bethe same or different polymer (or mix of polymers) in the same ordifferent amount, concentration, and/or weight percentage. In someembodiments, the control region 300 comprises a polymer and thetherapeutic region 200 does not include a polymer. In some embodiments,the therapeutic region 200 comprises a polymer and the control region300 does not include a polymer. At least as used in this section, “thepolymer” applies to a polymer that may be used in the therapeutic region200 and/or in the control region 300.

The bioresorbable polymers used in the present technology preferablyhave a predetermined degradation rate. The terms “bioresorbable,” or“bioabsorbable,” mean that a polymer will be absorbed within thepatient's body, for example, by a cell or tissue. These polymers are“biodegradable” in that all or parts the polymeric film will degradeover time by the action of enzymes, by hydrolytic action and/or by othersimilar mechanisms in the patient's body. In various embodiments, thebiodegradable, bioresorbable polymer film can break down or degradewithin the body to non-toxic components while a therapeutic agent isbeing released. Polymers used as base components of the depots of thepresent technology may break down or degrade after the therapeutic agentis fully released. The bioresorbable polymers are also “bioerodible,” inthat they will erode or degrade over time due, at least in part, tocontact with substances found in the surrounding tissue, fluids or bycellular action.

Criteria for the selection of the bioresorbable polymer suitable for usein the present technology include: 1) in vivo safety andbiocompatibility; 2) therapeutic agent loading capacity; 3) therapeuticagent releasing capability; 4) degradation profile; 5) potential forinflammatory response; and 6) mechanical properties, which may relate toform factor and manufacturability. As such, selection of thebioresorbable polymer may depend on the clinical objectives of aparticular therapy and may involve trading off between competingobjectives. For example, PGA (polyglycolide) is known to have arelatively fast degradation rate, but it is also fairly brittle.Conversely, polycaprolactone (PCL) has a relatively slow degradationrate and is quite elastic. Copolymerization provides some versatility ifit is clinically desirable to have a mix of properties from multiplepolymers. For biomedical applications, particularly as a biodegradabledepot for drug release, a polymer or copolymer using at least one ofpoly(L-lactic acid) (PLA), PCL, and PGA are generally preferred. Thephysical properties for some of these polymers are provided in Table 3below.

TABLE 3 Elastic Tensile Tensile Degradation Tg Tg Modulus StengthElongation Time (° C.) (° C.) (GPa) (MPa) (%) (months) Materials [1] [1][1] [1] [1] [2] PLA 45-60 150-162 0.35-3.5  21-60 2.5-6   12-16  PLLA55-65  17-200 2.7-4.14 15.5-150  3-10 >24 PDLA 50-60 — 1.0-3.45 27.6-50 2-10 6-12 PLA/PGA 40-50 — 1.0-4.34 41.4-55.2 2-10  3 (50:50) PGA 35-45220-233 6.0-7.0   60-99.7 1.5-20  6-12 PCL −60-−65 58-65 0.21-0.44 20.7-42  300-1000 >24

In many embodiments, the polymer may include polyglycolide (PGA). PGA isone of the simplest linear aliphatic polyesters. It is prepared by ringopening polymerization of a cyclic lactone, glycolide. It is highlycrystalline, with a crystallinity of 45-55%, and thus is not soluble inmost organic solvents. It has a high melting point (220-225° C.), and aglass transition temperature of 35-40° C. (Vroman, L., et al.,Materials, 2009, 2:307-44). Rapid in vivo degradation of PGA leads toloss of mechanical strength and a substantial local production ofglycolic acid, which in substantial amounts may provoke an inflammatoryresponse.

In many embodiments, the polymer may include polylactide (PLA). PLA is ahydrophobic polymer because of the presence of methyl (—CH3) side groupsoff the polymer backbone. It is more resistant to hydrolysis than PGAbecause of the steric shielding effect of the methyl side groups. Thetypical glass transition temperature for representative commercial PLAis 63.8° C., the elongation at break is 30.7%, and the tensile strengthis 32.22 MPa (Vroman, 2009). Regulation of the physical properties andbiodegradability of PLA can be achieved by employing a hydroxy acidsco-monomer component or by racemization of D- and L-isomers (Vroman,2009). PLA exists in four forms: poly(L-lactic acid) (PLLA),poly(D-lactic acid) (PDLA), meso-poly(lactic acid) and poly(D,L-lacticacid) (PDLLA), which is a racemic mixture of PLLA and PDLA. PLLA andPDLLA have been the most studied for biomedical applications.

Copolymerization of PLA (both L- and D,L-lactide forms) and PGA yieldspoly(lactide-co-glycolide) (PLGA), which is one of the most commonlyused degradable polymers for biomedical applications. In manyembodiments, the polymer may include PLGA. In many embodiments, thepolymer may include PLGA. Since PLA and PGA have significantly differentproperties, careful choice of PLGA composition can enable optimizationof performance in intended clinical applications. Physical propertymodulation is even more significant for PLGA copolymers. When acomposition is comprised of 25-75% lactide, PLGA forms amorphouspolymers which are very hydrolytically unstable compared to the morestable homopolymers. This is demonstrated in the degradation times of50:50 PLGA, 75:25 PLGA, and 85:15 PLGA, which are 1-2 months, 4-5 monthsand 5-6 months, respectively. In some embodiments, the polymer may be anester-terminated poly (DL-lactide-co-glycolide) (“PLGA”) in a molarratio of 50:50 (DURECT Corporation).

In some embodiments, the polymer may include polycaprolactone (PCL). PCLis a semi-crystalline polyester with high organic solvent solubility, amelting temperature of 55-60° C., and glass transition temperature of−54° C. (Vroman, 2009). PCL has a low in vivo degradation rate and highdrug permeability, thereby making it more suitable as a depot for longerterm drug delivery. For example, Capronor® is a commercial contraceptivePCL product that is able to deliver levonorgestrel in vivo for over ayear. PCL is often blended or copolymerized with other polymers likePLLA, PDLLA, or PLGA. Blending or copolymerization with polyethersexpedites overall polymer erosion. Additionally, PCL has a relativelylow tensile strength (˜23 MPa), but very high elongation at breakage(4700%), making it a very good elastic biomaterial. PCL also is highlyprocessable, which enables many potential form factors and productionefficiencies.

Suitable bioresorbable polymers and copolymers for use in the presenttechnology include, but are not limited to, poly(alpha-hydroxy acids),poly(lactide-co-glycolide)(PLGA or DLG),poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL),poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC),polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB),polyhydroxyalkanoates (PHA), poly(phosphazene), polyphosphate ester),poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS),polyethylene oxide, polypropylene fumarate, polyiminocarbonates,poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone)(PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate),poly(glycolide-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamicacid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerolsebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene,ethyl glycinate polyphosphazene, polycaprolactone co-butylacrylate, acopolymer of polyhydroxybutyrate, a copolymer of maleic anhydride, acopolymer of poly(trimethylene carbonate), polyethylene glycol (PEG),hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides(such as hyaluronic acid, chitosan and starch), proteins (such asgelatin and collagen) or PEG derivatives and copolymers thereof. Othersuitable polymers or copolymers include polyaspirins, polyphosphagenes,collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosans,gelatin, alginates, albumin, fibrin, vitamin E analogs, such as alphatocopheryl acetate, d-alpha tocopheryl succinate, D-lactide,D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL),D,L-lactide-glycolide-caprolactone (DL-G-CL), dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate)hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose orsalts thereof, Carbopol®, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, or combinations thereof.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

As described above, it may be desirable in certain clinical applicationsusing depots for controlled delivery of therapeutic agents to usecopolymers comprising at least two of PGA, PLA, PCL, PDO, and PVA. Theseinclude, for example, poly(lactide-co-caprolactone) (PLCL) (e.g. havinga PLA to PCL ratio of from 90:10 to 60:40) or its derivatives andcopolymers thereof, poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g.having a DL-PLA to PCL ratio of from 90:10 to 50:50) or its derivativesand copolymers thereof, poly(glycolide-co-caprolactone) (PGCL) (e.g.having a PGA to PCL ratio of from 90:10 to 10:90) or its derivatives andcopolymers thereof, or a blend of PCL and PLA (e.g. a ratio blend of PCLand PLA having a wt:wt ratio of 1:9 to 9:1). In one preferredembodiment, the bioresorbable polymer comprises a copolymer ofpolycaprolactone (PCL), poly(L-lactic acid) (PLA) and polyglycolide(PGA). In such a preferred embodiment, the ratio of PGA to PLA to PCL ofthe copolymer may be 5-60% PGA, 5-40% PLA and 10-90% PCL. In additionalembodiments, the PGA:PLA:PCL ratio may be 40:40:20, 30:30:50, 20:20:60,15:15:70, 10:10:80, 50:20:30, 50:25:25, 60:20:20, or 60:10:30. In someembodiments, the polymer is an ester-terminated poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10(DURECT Corporation).

In some embodiments, a terpolymer may be beneficial for increasing thedegradation rate and ease of manufacturing, etc.

To minimize the size of a bioresorbable depot, it is generally preferredto maximize the loading of therapeutic agent in the polymer to achievethe highest possible density of therapeutic agent. However, polymercarriers having high densities of therapeutic agent are more susceptibleto burst release kinetics and, consequently, poor control over timerelease. As described above, one significant benefit of the depotstructure described herein, and particularly the control region featureof the depot, is the ability to control and attenuate the therapeuticagent release kinetics even with therapeutic agent densities that wouldcause instability in other carriers. In certain embodiments, thetherapeutic agent loading capacity includes ratios (wt:wt) of thetherapeutic agent to biodegradable polymer of approximately 1:3, 1:2,1:1, 3:2, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, or16:1. In some embodiments, it may be desirable to increase thetherapeutic effect or potency of the therapeutic agent released from thedepot described herein while still maintaining the same or similarpolymer to therapeutic agent ratio. This can be accomplished by using anessentially pure form of the therapeutic agent as opposed to a saltderivative. Additionally or alternatively, the therapeutic agent can bemixed with clonidine or epinephrine, which are known to increase thetherapeutic effect of certain drugs.

When implanted in a patient's joint (for example, a knee joint), thebiodegradable depot described above may be positioned in the joint suchthat it will be articulating throughout the duration of release. So asto avoid premature release of the analgesic, it is desirable for thedepot to have a threshold level of mechanical integrity and stabilityuntil most of the analgesic has been released. While it may be desirableto maximize the loading of therapeutic agent in the biodegradable depot,as described above, such maximization can typically be at the expense ofmechanical integrity and stability of the depot. Given the high dosageof anesthetic necessary to provide analgesia through both the acute andsubacute postoperative pain periods and limited space in the knee, it isdesirable for the depot described herein to have a high density loadingof anesthetic while still maintaining sufficient mechanical integrityand stability in the knee. The layered structure and, particularly, thepresence of the control region provide some safeguard against thepremature release of anesthetic. Moreover, the use of heat compressionin the manufacturing process enables substantial loading of anestheticinto the therapeutic region while creating a thermal bond between thetherapeutic region and control region, thereby preventing delamination,and a consequent uncontrolled release of drug, when the depot issubjected to mechanical stress in the knee.

It is generally desirable that the implanted polymer fully degradefollowing complete delivery of the therapeutic agent. Full degradationis preferred because, unless the implanted polymer provides somestructural function or support, the clinical practitioner would have toreconcile leaving in a foreign body with no functional purpose, whichcould be a source of inflammation or infection, or perform anothersurgery simply to remove the remaining polymer. As an alternative tofull degradation, it would be desirable for any remaining polymer to befully encapsulated by the body.

The degradation of an implanted polymer consists essentially of twosequential processes: diffusion of an aqueous solution (i.e.,physiological fluids) followed by hydrolytic degradation. Degradationusually takes one of two forms: (1) surface erosion; and (2) bulkdegradation. Surface erosion of a polymer occurs when the polymer erodesfrom the surface inward, where hydrolytic erosion at the surface isfaster than the ingress of water into the polymer. Conversely, bulkdegradation occurs throughout the entire polymer, where water penetratesand degrades the interior of the material faster than the surface canerode. Polymers such as PLA, PGA, PLGA and PCL all resorb into the bodyvia bulk degradation.

The time necessary for complete degradation can vary greatly based onthe material selected and the clinical performance requirements of thedepot. For example, in the case of treating and managing postoperativepain, it may be desirable for the polymer depot to release therapeuticagent (i.e., an analgesic) for anywhere from 5 to 30 days. In the caseof treating or preventing infection of a prosthetic joint (e.g., knee orhip implant), it may be desirable for the polymer depot to release ananti-infective agent for anywhere from 2 to 4 months. Alternatively,even if the entire amount of therapeutic agent loaded into the polymerhas been released, it may be desirable for the polymer to degrade over alonger period than the duration of drug release. For example, rapiddegradation can often make the polymer brittle and fragile, therebycompromising mechanical performance, or provoking an inflammatoryresponse from the body. In particular, it may be desirable, in certainclinical applications, to have an embodiment wherein degradation of thepolymer commenced only after release of substantially all of thetherapeutic agent.

In certain embodiments of the present technology, it may be desirablefor the polymer to fully resorb into the body after substantially alltherapeutic agent loaded therein is released. In certain embodiments,this degradation can be as short as 1 month. Alternatively, in otherembodiments, full degradation could take as long as 2 months, 3 months,4 months, 6 months, 9 months or 12 months. In some embodiments, thebioresorbable polymer substantially degrades in vivo within about onemonth, about two months, about three months, about four months, aboutfive months or about six months. In some embodiments, it may bedesirable for full degradation to be 6 months such that the mechanicalproperties of the implanted polymer are preserved for the first 2 monthsfollowing implantation.

Core Acidification

Traditional biodegradable orthopedic implants often lead to tissueinflammation due to a phenomenon known as “core acidification.” Forexample, as shown schematically in FIG. 17, polymer implants having athickness greater than 1 mm degrade by bulk erosion (i.e., degradationoccurs throughout the whole material equally; both the surface and theinside of the material degrade at substantially the same time). As thepolymer degrades, lactate accumulates at an internal region of theimplant. Eventually, because of the high pH in the internal region ofthe implant, the lactate becomes lactic acid. The accumulated lacticacid will invariably release into the body, thereby provoking aninflammatory response. FIG. 18, for example, is a scanning electronmicroscope (“SEM”) image of a polymer tablet of the prior art after 20days of degradation. Inflammation in and around a prosthetic joint maybe particularly concerning because of the risk of inflammation-inducedosteolysis, which may cause a loosening of the newly implanted joint.Moreover, core acidification causes extracellular pH to drop, which thencauses the amount of free base bupivacaine to drop. Only free basebupivacaine can cross the lipid bilayer forming the cell membrane intothe neuron. Once bupivacaine crosses into the neuron the percent ofbupivacaine HCl increases. It is the bupivacaine HCl form that is activeby blocking sodium from entering the neuron thus inducing analgesia.Thus, any reduction in extracellular pH (for example, via coreacidification) slows transfer of the analgesic into the neuron, therebyreducing or altogether eliminating the therapeutic effects of theanalgesic.

The degree of core acidification is determined in large part by thegeometry and dimensions of the polymer implant. (See, e.g., Grizzi etal., Hydrolytic degradation of devices based on poly(dl-lactic acid)size-dependence, BIOMATERIALS, 1995, Vol. 16 No. 4, pp. 305-11; Fukuzakiet al., in vivo characteristics of high molecular weightcopoly(l-lactide/glycolide) with S-type degradation pattern forapplication in drug delivery systems, Biomaterials 1991, Vol. 12 May,pp. 433-37; Li et al., Structure-property relationships in the case ofdegradation of massive alipathic poly-(α-hydroxy acids) in aqueousmedia, JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE I (1990), pp.123-130.) For example, degradation in more massive monolithic devices(mm-size scales and greater) proceeds much more rapidly in theirinterior than on their surface, leading to an outer layer of slowlydegrading polymer entrapping more advanced internal degradation productsfrom interior zone autocatalysis (so-called “S-type” non-linear kineticdegradation profile.). In contrast to a thicker film, a thin film ofless than 1 mm thickness will typically degrade via surface erosion,wherein the lactate resulting from degradation will not accumulate inthe interior of the film. Thin films, because of their high surface areato volume ratios, are known to degrade uniformly and do not lead to coreacidification. (See Grizzi et al.)

As shown schematically in FIG. 18, the depots of the present technologymay shed up to 50%, 60%, 70% or 80% of their individual mass (anestheticand releasing agent) over the course of releasing the anesthetic (e.g.,5 days, 7 days, 10 days, 14 days, 20 days, 30 days, etc.), resulting ina highly porous, mesh-like system that—at least for the purpose ofdegradation—behaves like a thin-film because of its high surface area tovolume ratio. Body fluids will invade the highly porous polymer carrierto degrade the remaining polymer via surface erosion, thereby avoidingcore acidification and the resulting inflammatory response. Withoutbeing bound by theory, it is believed that the drug core matrix of thetherapeutic region becomes highly porous as degradation continues. Forexample, FIGS. 19B and 19C are scanning electron microscope (“SEM”)images showing the therapeutic region before and after elution,respectively. However, even after the release of therapeutic agent,there is still a clear porous structure left through which water andacid can diffuse effectively. Thus, depots 100 of the present technologyhaving a thickness greater than about 1 mm degrade like a thin film, andsurprisingly do not exhibit core acidification.

E. Releasing Agent

In many implantable drug eluting technologies, the depot provides aninitial, uncontrolled burst release of drug followed by a residualrelease. These drug release kinetics may be desirable in certainclinical applications, but may be unavoidable even when undesirable.Hydrophilic drugs loaded in a polymer carrier will typically provide aburst release when exposed to physiologic fluids. This dynamic maypresent challenges, particularly when it is desirable to load a largevolume of drug for controlled, sustained in vivo administration. Forexample, although it may be desirable to implant several days or weeks'worth of dosage to achieve a sustained, durable, in vivo pharmacologicaltreatment, it is imperative that the therapeutic agent is released asprescribed, otherwise release of the entire payload could result insevere complications to the patient.

To achieve finer control over the release of the therapeutic agent whenexposed to fluids, the depots 100 of the present technology may includea releasing agent. In some embodiments, both the therapeutic region 200and the control region 300 include a releasing agent (or mix ofreleasing agents), which can be the same or different releasing agent(or mix of releasing agents) in the same or different amount,concentration, and/or weight percentage. In some embodiments, thecontrol region 300 includes a releasing agent and the therapeutic region200 does not include a releasing agent. In some embodiments, thetherapeutic region 200 includes a releasing agent and the control region300 does not include a releasing agent. At least as used in thissection, “the releasing agent” applies to a releasing agent that may beused in the therapeutic region 200 and/or in the control region 300.

The type and/or amount of releasing agent within the therapeutic region200 and/or control region 300 may be varied according to the desiredrelease rate of the therapeutic agent into the surrounding biologicalfluids. For example, choosing releasing agents with differentdissolution times will affect the rate of release. Also, the weightpercentage of releasing agent in a region of polymer will influence thenumber and the size of the diffusion openings subsequently formed in thepolymer, thereby affecting the rate of therapeutic agent release fromthe depot 100 (e.g., the greater the weight percentage of releasingagent, the faster the release). The presence of releasing agent inselect regions also influences the release rate of therapeutic agent.For example, a depot with releasing agent in the control region 300and/or therapeutic region 200 will generally release therapeutic agentat a higher rate compared to a depot with no releasing agent. Similarly,releasing agent in both the control region 300 and the therapeuticregion 200 will generally release therapeutic agent at a higher ratethan when releasing agent is in the control region alone.

In certain embodiments of the present technology, the layer-by-layerratio of releasing agent to bioresorbable polymer can be adjusted tocontrol the rate of therapeutic agent released from the depot 100. Forexample, in many embodiments of the present technology, the depot 100includes a therapeutic region 200 having a weight percentage ofreleasing agent that is different than the weight percentage of thereleasing agent in the control region 200. For example, the therapeuticregion 200 may have a greater or lesser weight percentage of releasingagent than the control region 300. In some embodiments, the controlregion 300 may have a weight percentage of releasing agent that is atleast 2 times greater than the weight percentage of the releasing agentin the therapeutic region 200. In some embodiments, the control region300 may have a weight percentage of releasing agent that is at least3-20 times greater than the weight percentage of the releasing agent inthe therapeutic region 200.

In many embodiments of the present technology, the releasing agent is asurfactant. Unlike the use as a releasing agent as described herein,surfactants are usually used to control the dispersions, flocculationand wetting properties of a drug or polymer. Fundamentally, surfactantsoperate on the interface between the polymer and drug or the interfacebetween the drug and biological membrane. Depending on the type offormulation, surfactants typically play a role in several aspects ofdrug delivery: (1) solubilization or stabilization of hydrophobic drugsby lowering the entropic cost of solvating hydrophobic drug throughcomplexation with drug molecules in solution (C. Bell and K. A. Woodrow,ANTIMICROB. AGENTS CHEMOTHER., 2014, 58:8, 4855-65); (2) improvement ofthe wetting of tablet or polymer for fast disintegration (M. Irfan, etal., SAUDI PHARM. J., 2016, 24, 537-46); (3) formation of colloidal drugdelivery systems, such as reverse micelles, vesicles, liquid crystaldispersions, nanoemulsions and nanoparticles (M. Fanun, Colloids in DrugDelivery, 2010, p. 357); and (4) improvement the bioperformance of drugsby altering the permeability of biological membrane and consequentlydrug penetration/permeation profile (S. Jain, et al., Lipid BasedVesicular Drug Delivery Systems, 2014, Vol. 2014, Article ID 574673).

In order to illustrate the unique aspects of using a releasing agent inthe polymeric control region to form microchannels in the presenttechnology, it is helpful to explain the more common approach of usinghydrophilic molecules to enhance drug release. Conventionally, drugrelease is enhanced by creating a larger surface area in order toincrease contact between the drug and the bodily fluid, therebyaccelerating drug release. The most common pore-forming mechanism is touse non-surfactant hydrophilic molecules as pore-forming agents inpolymer layers, either as a coating layer or a free-standing film(Kanagale, P., et al., AAPS PHARM. SCI. TECH., 2007; 8(3), E1-7).Usually, pores are pre-formed by blending hydrophilic molecules withpolymer, then removing the hydrophilic molecules by contact with water.However, when hydrophilic molecules are blended with hydrophobicpolymer, the molecules tend to form hydrophilic domains and hydrophobicdomains, which are energetically favorable due to the increase inentropy. When the film contacts water, hydrophilic domains are removedand replaced with large pores. The rate of drug release in this case issolely controlled by the porosity of the film and the resultingincreased total surface area. The typical drug release curve in thiscase has a high, uncontrolled initial burst followed with a very slowrelease of residual drug afterwards.

Previously, when non-surfactant hydrophilic molecules are mixed into thepolymer and then removed, a film with a porous structure is created.This porous layer reduces mechanical strength and elasticity, making itless suitable for certain applications. Additionally, this structuredoes not withstand heat compression bonding of the film because thepores would collapse. The loss of porous structure during heatcompression negates the original intent of using the hydrophilicmolecule, thus resulting in a densely packed film without any enhancedtherapeutic agent release capability.

Further, if the hydrophilic molecule remains in the polymer layer duringheat compression, the dissolution of the hydrophilic molecule in vivocauses the formation of very large pores, approximately 3-10 μm indiameter. Such large pores provide a large surface area, thereby causinga burst release of drug. In contrast to the use of hydrophilicmolecules, the use of a surfactant as a releasing agent in the presenttechnology enables the formation of microchannels approximately 5-20nanometers in diameter, which is two orders of magnitude smaller thanthe pores resulting from the use of hydrophilic molecules. This allowstight control of the drug release by diffusion and, if desirable,without an uncontrolled burst release upon implantation. Additionally,use of a surfactant as a releasing agent allows the agent to remainpresent in the polymer prior to use and no pre-formed pores are created.This approach is particularly advantageous because the polymer'smechanical properties are preserved, thereby allowing the polymer to beeasily processed and worked into different configurations.

In the present technology, the releasing agent is pre-mixed into thebioresorbable polymer such that each layer of polymer is contiguous anddense. The depot 100 is then formed when these layers are bondedtogether via heat compression without any adverse impact to thefunctional capabilities of the film. When the densely packed film isultimately implanted, the releasing agent dissolves to enable efficient,controlled release of the therapeutic agent.

In some embodiments, the releasing agent comprises a polysorbate.Polysorbate is commonly used in the pharmaceutical industry as anexcipient and solubilizing agent. Polysorbate is a non-ionic surfactantformed by the ethoxylation of sorbitan followed by esterification bylauric acid. Polysorbate 20 [IUPAC name: polyoxyethylene(20)sorbitanmonolaurate] contains a mixture of ethoxylated sorbitan with 20 repeatunits of polyethylene glycol distributed among four different sites inthe sorbitan molecule. Common commercial names include Tween™ and Tween20™ (Croda International Plc, Goole, East Yorkshire, UK) and Alkest® TW20 (Oxiteno, Houston, Tex.).

Polysorbate is often utilized to improve oral bioavailability of apoorly water-soluble/hydrophobic drug. For example, polysorbate was usedto improve bioavailability of active molecules that possess lowsolubility and/or intestinal epithelial permeability and it was observedthat the bioavailability of this poorly water-soluble drug was greatlyenhanced in a formulation with polysorbate or similar surfactants.(WO2008/030425; Breslin; Merck.) Akbari, et al., observed that using thehydrophilic carrier polyethylene glycol (PEG) along with polysorbateleads to faster an oral enhanced drug release rate because thepolysorbate brings the drug in close contact with the PEG. (Akbari, J.,et al., ADV. PHARM. BULL., 2015, 5(3): 435-41.)

Polysorbate also functions as a water-soluble emulsifier that promotesthe formation of oil/water emulsions. For example, the drug famotidineis known to have high solubility in water but low in vivo permeability.Polysorbate was used in an oral microemulsion formulation for enhancingthe bioavailability of famotidine. (Sajal Kumar Jha, et al., IJDDR,2011, 3(4): 336-43.) Polysorbate is also used as a wetting agent toachieve rapid drug delivery. For example, Ball et al., achieved rapiddelivery of maraviroc via a combination of a polyvinylpyrrolidone (PVP)electrospun nanofiber and 2.5 wt % Tween 20, which allowed for thecomplete release of 28 wt % maraviroc in just six minutes. It wasbelieved that use of Tween 20 as a wetting agent allowed water topenetrate the PVP nanofiber matrix more quickly, thereby increasing therate of drug release. (Ball, C., et al., ANTIMICROB. AGENTSCHEMOTHERAPY, 2014, 58:8, 4855-65.)

As described above, in order to improve drug release in certain polymercarriers, hydrophilic polymers, such as polysorbate, have been added tothese carriers to accelerate or to enhance drug release frombiocompatible polymers such as polyethylene glycol (PEG) in oralformulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3):435-441). However, these formulations are intended to provide animmediate release of a hydrophobic drug into a hydrophilic environment(the in vivo physiologic fluid), not a variable or sustained controlledrelease as part of a control region.

In some embodiments, the releasing agent is polysorbate 20, commerciallyknown as Tween 20™. Other releasing agents suitable for use in thepresent technology include polysorbates, such as Polysorbate 80,Polysorbate 60, Polysorbate 40, and Polysorbate 20; sorbitan fatty acidesters, such as sorbitan monostearate (Span 60), sorbitan tristearate(Span 65), sorbitane trioleate (Span 85), sorbitan monooleate (Span 80),sorbitan monopalmitate, sorbitan monostearate, sorbitan monolaurate,sorbitan monopalmitate, sorbitan trioleate, and sorbitan tribehenate;sucrose esters, such as sucrose monodecanoate, sucrose monolaurate,sucrose distearate, and sucrose stearate; castor oils such aspolyethoxylated castor oil, polyoxyl hydrogenated castor oil, polyoxyl35 castor oil, Polyoxyl 40 Hydrogenated castor oil, Polyoxyl 40 castoroil, Cremophor® RH60, and Cremophor® RH40; polyethylene glycol esterglycerides, such as Labrasol®, Labrifil® 1944; poloxamer;polyoxyethylene polyoxypropylene 1800; polyoxyethylene fatty acidesters, such as Polyoxyl 20 Stearyl Ether, diethylene glycol octadecylether, glyceryl monostearate, triglycerol monostearate, Polyoxyl 20stearate, Polyoxyl 40 stearate, polyoxyethylene sorbitanmonoisostearate, polyethylene glycol 40 sorbitan diisostearate; oleicacid; sodium desoxycholate; sodium lauryl sulfate; myristic acid;stearic acid; vitamin E-TPGS (vitamin E d-alpha-tocopherol polyethyleneglycol succinate); saturated polyglycolized glycerides, such asGelucire® 44/14 and and Gelucire® 50/13; and polypropoxylated stearylalcohols such as Acconon® MC-8 and Acconon® CC-6.

Diffusion Openings

The channels or voids formed within the therapeutic region 200 and/orcontrol region 300 by dissolution of the releasing agent may be in theform of a plurality of interconnected openings or pores and/or aplurality of interconnected pathways. In some embodiments, one or moreof the channels may be in the form of discrete pathways, channels, oropenings within the respective therapeutic and/or control region.Depending on the chemical and material composition of the therapeuticand control regions, one or more of the formed channels may extend: (a)from a first end within the therapeutic region to a second end alsowithin the therapeutic region; (b) from a first end within thetherapeutic region to a second end at the interface of the therapeuticregion and the control region; (c) from a first end within thetherapeutic region to a second end within the control region; (d) from afirst end within the therapeutic region through the control region to asecond end at an outer surface of the control region; (e) from a firstend at the interface between the therapeutic region and the controlregion through the control region to a second end within the controlregion; (f) from a first end at the interface between the therapeuticregion and the control region to a second end at an outer surface of thecontrol region; (g) from a first end within the control region to asecond end also within the control region; and (h) from a first endwithin the control region to a second end at an outer surface of thecontrol region. Moreover, one or more of the channels may extend betweentwo or more microlayers of the therapeutic region and/or control region.

F. Constituent Ratios

In some embodiments, the ratio of the polymer in the control region 300to the releasing agent in the control region 300 is at least 1:1. Insome embodiments, the ratio may be at least 1.5:1, at least 2:1, atleast 2.5:1, or at least 3:1.

In some embodiments, a ratio of the mass of the therapeutic agent in thedepot 100 to the polymer mass of the depot is at least 1:1, at least2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least7:1, at least 8:1, at least 9:1, at least 10:1, at least 11:1, at least12:1, at least 13:1, at least 14:1, at least 15:1, or at least 16:1.

In some embodiments, the ratio of releasing agent to polymer totherapeutic agent in the therapeutic region 200 is of from about0.1:10:20 to about 2:10:20, and in some embodiments of from about0.1:10:20 to about 1:10:20, and in some embodiments of from about0.1:10:20 to about 0.5:10:20.

In some embodiments, the ratio of releasing agent to polymer in thecontrol region 300 is of from about 1:2 to about 1:10. In someembodiments, one or more of the control regions may have a ratio ofreleasing agent to polymer of 1:2, and one or more of the other controlregions may have a ratio of releasing agent to polymer of 1:10

G. Selected Depot Embodiments Including a Base Region

In some embodiments, the depot 100 may be configured to release thetherapeutic agent in an omnidirectional manner. In other embodiments,the depot may include one or more base regions covering one or moreportions of the therapeutic region 200 and/or control region 300, suchthat release of the therapeutic agent is limited to certain directions.The base region may provide structural support for the depot. The baseregion may comprise a low porosity, high density of bioresorbablepolymer configured to provide a directional release capability to thedepot. In this configuration, the substantial impermeability of this lowporosity, high density polymer structure in the base region blocks orimpedes the passage of agents released from the therapeutic region 200.Accordingly, the agents released from the therapeutic region 200 take apath of less resistance through the control region 300 opposite from thebase region, particularly following the creation of diffusion openingsin the control region 300.

An example a depot 100 of the present technology having a base region isshown in FIG. 16A. The base region may comprise a low porosity, highdensity of bioresorbable polymer configured to provide a directionalrelease capability to the multi-region depot. In this configuration, thelow porosity, high density polymer structure in the base region blocksor impedes passage of agents release from the therapeutic region 200.Accordingly, the agents released from the therapeutic region 200 take apath of lesser resistance through the control region opposite from thebase region, particularly following the creation of channels in thecontrol region. In an additional embodiment, the porosity of otherregions of the multi-region depot can be varied to facilitate therelease of therapeutic agent. For example, in this embodiment, the baseregion, the therapeutic region 200, and the control region 300 of themulti-region depot depicted in FIG. 16A may have different porositiesranging from low porosity in the base region to higher porosities in thetherapeutic agent and control regions to facilitate the release oftherapeutic agent from the multi-region depot. In additionalembodiments, the porosities of the edges of the multi-region depot, orwithin portions of any of the individual regions, can be varied toproperly regulate or manipulate the release of therapeutic agent.

In the embodiment depicted in FIG. 16B, the multi-region depot providesfor a bilateral or bidirectional release of therapeutic agent. Thisbidirectional release capability is accomplished through symmetricregioning about a high density base region, wherein, as described above,the therapeutic agent releases along a path of less resistance, therebyreleasing away from the high density base region. More specifically,disposed on one side of the base region is a control region 300 a and atherapeutic region 200 a and, disposed on the other side of the baseregion, is a control region 300 b and a therapeutic region 200 b thatare substantially similar to the pair on the other side. These pairs oneither side of the base region are configured to produce substantiallyequivalent, bidirectional release of therapeutic agent. In an alternateembodiment, a bidirectional release that is not equivalent (i.e., thetherapeutic agent and/or rate of release in each direction is not thesame) may be accomplished by asymmetric regioning, whereby the controlregion and therapeutic region pairs on either side of the base regionare substantially different.

In additional embodiments, it may be desirable for the multi-regiondepot to release multiple therapeutic agents. This capability can beparticularly useful when multimodal pharmacological therapy isindicated. In the embodiment shown in FIG. 16C, the multi-region depotcomprises a topmost or outermost control region 300 a, a firsttherapeutic region 200 a adjacent to the control region, a secondtherapeutic region 200 b adjacent to the first therapeutic region 200 a,and a base region adjacent to the second therapeutic region 200 b. Inthis embodiment, the first therapeutic region 200 a and the secondtherapeutic region 200 b comprise a first therapeutic agent and a secondtherapeutic agent, respectively. In certain embodiments, the first andsecond therapeutic agents are different. In one embodiment, themulti-region depot is configured to release the first and secondtherapeutic agents in sequence, simultaneously, or in an overlappingfashion to yield a complementary or synergistic benefit. In thisconfiguration, the presence and function of the control region 300 a mayalso ensure consistent and, if desired, substantially even release ofmultiple therapeutic agents residing beneath. Since many conventionaldrug delivery devices can fail to provide an even release of multipledrugs with different molecular weights, solubility, etc., the role ofthe control region in achieving a substantially even release ofdifferent therapeutic agents can be a significant advantage.

In some embodiments, the first therapeutic agent and second therapeuticagent are the same therapeutic agent but are present in the first andsecond therapeutic regions, respectively, in different relativeconcentrations to represent different dosages to be administered. Insome embodiments, the first and second therapeutic agents of the firstand second therapeutic regions, respectively, may have no clinicalassociation or relationship whatsoever. For example, in an embodimentfor use as part of a total joint replacement (e.g., total kneearthroplasty, total hip arthroplasty) or other surgical procedure, itmay be clinically desirable to administer in the vicinity of thesurgical site both an analgesic (e.g., local anesthetic) to treat andbetter manage postoperative pain for several days or weeks following thesurgery and an antibiotic to treat or prevent surgical site infectionassociated with the surgery or implanted prosthesis (if any) for severalweeks or months following the surgery. In this embodiment, the firsttherapeutic region 200 a may comprise a therapeutically effective doseof local anesthetic to substantially provide pain relief for no lessthan 3 days and up to 15 days following the surgery and the secondtherapeutic region 200 b may comprise a therapeutically effective doseof antibiotics to substantially provide a minimally effectiveconcentration of antibiotic in the vicinity of the surgical site for upto three months following the surgery.

In some embodiments, as shown in FIG. 16D, the depot 100 comprises afirst dosage region and a second dosage region, wherein the first andsecond dosage regions correspond to first and second dosage regimens.More specifically, each dosage region comprises a control region andtherapeutic region pair, wherein each pair is configured for controlledrelease of a therapeutic agent from the therapeutic region 200 a, 200 bin accordance with a predetermined dosage regimen. For example, intreating and/or managing postoperative pain, it may be desirable for themulti-region depot to consistently release 50-400 mg/day of localanesthetic (e.g., bupivacaine, ropivacaine and the like) for at least2-3 days following surgery (i.e., first dosage regimen) and then releasea local anesthetic at a slower rate (e.g., 25-200 mg/day) for the next 5to 10 days (i.e., second dosage regimen). In this exemplary embodiment,the first dosage region, and the control region and therapeutic regionpair therein, would be sized, dimensioned, and configured such that themulti-region depot releases the first therapeutic agent in a manner thatis consistent with the prescribed first dosage regimen. Similarly, thesecond dosage region, and the control region and therapeutic region pairtherein, would be sized, dimensioned and configured such that themulti-region depot releases the second therapeutic agent in a mannerthat is consistent with the prescribed second dosage regimen. In anotherembodiment, the first and second dosage regions may correspond to dosageregimens utilizing different therapeutic agents. In one embodiment, themulti-region depot 100 is configured to administer the first and seconddosage regimens in sequence, simultaneously, or in an overlappingfashion to yield a complementary or synergistic benefit. In an alternateembodiment of this scenario, the first and second dosage regimens,respectively, may have no clinical association or relationshipwhatsoever. For example, as described above with respect to theembodiment depicted in FIG. 16C, the first dosage regimen administeredvia the first dosage region may be treating or managing postoperativepain management and the second dosage regimen administered via thesecond dosage region may be treating or preventing infection of thesurgical site or implanted prosthesis (if any).

Certain embodiments of the present invention utilize delayed releaseagents. As illustrated in FIG. 16E, the depot 100 may include a delayregion as the outermost (i.e., topmost) region to the multi-region depotand adjacent to a control region 300 comprising a releasing agent. Thedelay region presents a barrier to physiologic fluids from reaching anddissolving the releasing agent within the control region. In oneembodiment, the delay region may comprise a delayed release agent mixedwith a bioresorbable polymer, but without a releasing agent. Delayedrelease agents are different from the releasing agents used in themulti-region depot of the invention. Delayed release agents dissolve inphysiological fluids more slowly than do releasing agents and thusprovide the possibility for release of a therapeutic agent a definedamount of time following implantation of the multi-region depot. Inembodiments where a delayed release agent is not present in the delayregion, it may take more time for the physiological fluids to traversethe delay region and contact the releasing agent. Only when thephysiological fluids make contact with the control region will thereleasing agent begin to dissolve, thus allowing the controlled releaseof the therapeutic agent. Delayed release agents may be advantageouslyused in the therapeutic methods of the invention wherein the therapeuticagent is not immediately required. For example, a nerve blocking agentmay be injected prior to a surgical procedure, numbing the entire areaaround a surgical site. The controlled release of a local anesthetic isnot required in such a surgery until the nerve block wears off.

Suitable delayed release agents for use in the present invention arepharmaceutically acceptable hydrophobic molecules such as fatty acidesters. Such esters include, but are not limited to, esters ofmyristoleic acid, sapienic acid, vaccenic acid, stearic acid, arachidicacid, palmitic acid, erucic acid, oleic acid, arachidonic acid, linoleicacid, linoelaidic acid, eicosapentaenoic acid, docosahexaenoic acid.Preferred esters include stearic acid methyl ester, oleic acid ethylester, and oleic acid methyl ester. Other suitable delayed releaseagents include tocopherol and esters of tocopherol, such as tocopherylnicotinate and tocopheryl linolate.

H. Example Methods of Manufacture

The depots of the present technology may be constructed using variouscombinations of biodegradable, bioresorbable polymer layers, whereinthese layers may include therapeutic agents, releasing agents, delayrelease agents, etc., in varying combinations and concentrations inorder to meet the requirements of the intended clinical application(s).In some embodiments, the polymer layers may be constructed using anynumber of known techniques to form a multilayer film of a particularconstruction. For example, a bioresorbable polymer and a therapeuticagent can be solubilized and then applied to the film via spray coating,dip coating, solvent casting, and the like. In an alternativeembodiment, a polymer layer for use as a control layer and/or atherapeutic agent layer can be constructed from electrospun nanofibers.

The depots 100 described herein may be constructed by placingtherapeutic regions (and/or sub-regions) and/or control regions (and/orsub-regions) on top of one another in a desired order and heatcompressing the resulting multilayer configuration to bond the layerstogether. Heat compression may be accomplished using any suitableapparatus known in the art. In one embodiment, the heat compressionprocess consists of utilizing a heat compressor (Kun Shan RebigHydraulic Equipment Co. Ltd., China), and heat compressing the stackedassembly of therapeutic 200 and/or control regions 300 at a temperaturethat is above room temperature (e.g., at least 30° C., 35° C., 40° C.,45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C.,90° C., 95° C., 100° C., 105° C., 110° C., 115° C., or 120° C., etc.)and a pressure of from about 0.01 MPa to about 1.0 MPa, or about 0.10MPa to about 0.8 MPa, or about 0.2 MPa to about 0.6 MPa. The inventorshave discovered that heating the therapeutic and control regions duringcompression (separately or after stacking) increases the therapeuticagent density in the depot 100. The inventors have also discovered thatheat compression at lower pressures enable higher drug densities.

Depending on the therapeutic dosage needs, anatomical targets, etc., thedepot 100 can be processed, shaped and otherwise engineered to produceform factors that can be administered to the patient by implantation inthe body by a clinical practitioner. For example, various configurationsof the film may be achieved by using a jig with a pre-shaped cutout,hand cutting the desired shape or both. Some of the form factorsproducible from the multilayer film for implantation into the bodyinclude: strips, ribbons, hooks, rods, tubes, patches, corkscrew-formedribbons, partial or full rings, nails, screws, tacks, rivets, threads,tapes, woven forms, t-shaped anchors, staples, discs, pillows, balloons,braids, tapered forms, wedge forms, chisel forms, castellated forms,stent structures, suture buttresses, coil springs, and sponges. Thedepot 100 may also be processed into a component of the form factorsmentioned above. For example, the depot 100 could be rolled andincorporated into tubes, screws tacks or the like. In the case of wovenembodiments, the depot 100 may be incorporated into a multi-layer wovenfilm wherein some of the filaments used are not the inventive device. Inone example, the depot 100 is interwoven with Dacron, polyethylene orthe like.

III. EXAMPLES

The following examples are offered by way of illustration and not by wayof limitation.

Example 1

Preparation of Bioresorbable Polymer/Drug Films.

Two depots of the present technology containing a high payload the localanesthetic bupivacaine were prepared according to the followingprocedures.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5, and referred to as “Control Layer A” in Table 4 below) and twoouter control layers (farthest from therapeutic region, such as 302 aand 302 d in FIG. 5, and referred to as “Control Layer B” in Table 4).The constituents of the therapeutic region and the control region aredetailed in Table 4.

TABLE 4 Single layer Therapeutic Region PolymerPoly(L-lactide-co-glycolic-co-ε-capro- lactone) (1760 mg) (Durect Corp,Birmingham) PLA to PGA to PCL ratio of from 90:5:5 to 60:30:10 ReleasingAgent Tween 20 (860 mg) (Sigma-Aldrich Pte Ltd; Singapore) Anestheticbupivacaine hydrochloride (3520 mg) (Xi'an Victory BiochemicalTechnology Co., Ltd.; Shaanxi, People's Republic of China)Anesthetic:Polymer 2:1 Releasing Agent:Poly- 5:10:20 mer:AnestheticControl Region Control Layer A innermost layer on top and bottom PolymerPLGACL (1056 mg) Releasing Agent Tween 20 (517 mg) Control Layer Boutermost layer on top and bottom Polymer PLGACL (1056 mg) ReleasingAgent Tween 20 (103 mg)

Therapeutic Region Components.

The therapeutic region was prepared by combining the polymer, releasingagent, anesthetic, and 3.15 mg of acetone (Merck; Kenilworth, N.J.) in aglass vial and mixing thoroughly. The resulting blend was poured onto aflat plate and compressed multiple times to form a thick film (about 1mm thick) upon drying.

Control Region Components.

The control region was prepared by combining the polymer, releasingagent, and 4.7 mg of acetone (Merck; Kenilworth, N.J.) in a glass vialand mixing thoroughly. The resulting blend was poured onto a flat plateand drawn by a film applicator to form a thin film (<200 μm thickness)upon drying.

For the sample depot, the single layer therapeutic region and the fourlayers comprising the control region were aligned and compressed by aheat compressor. The thin film was cut to form a 25 mm×15 mm sample withoverall film thickness <1.2 mm.

In Vitro Drug Release Testing of Bupivacaine Depot.

The purpose of this procedure was to measure the release of bupivacainefrom a bioresorbable polymer depot into a receiving fluid of 1×PBS. Eachrelease experiment was conducted in duplicate. The in vitro releaseprocedure consisted of placing a known size of film into an apparatuscontaining the receiving fluid. The in vitro release apparatus consistedof a 200 mL glass bottle. A receiving fluid in the amount of 100 mL wasadded to each sample bottle. During the release study, the apparatus wasplaced in a water bath maintained at 37±2° C. At predeterminedintervals, samples of the receiving fluid were removed and analyzed forbupivacaine concentration by UV-Visible Spectrophotometer.

FIG. 20 shows the drug release profile for the depots with effectivelyreduced initial burst effect and demonstrated a desirable consistentcontrolled release of drug.

Example 2A

Preparation of Bioresorbable Polymer/Drug Films.

Two depots of the present technology comprising the local anestheticbupivacaine were prepared as described in Example 1, except the depotsof the present example comprised two of the depots of Example 1 stackedon top of one another and heat compressed to form a new, thicker samplehaving an overall film thickness of about 2 mm (for example, see theconfiguration shown in FIG. 6).

In Vitro Drug Release Testing of Bupivacaine Depot.

in vitro drug release testing of the depots was performed as describedin Example 1.

Release Profiles.

FIG. 21 shows the average cumulative dose profiles of the bupivacainefilms. The graph shows controlled release of over 500 hours with theinitial 24-hour release of about 20%.

Example 2B

Preparation of Bioresorbable Polymer/Drug Films.

Two depots of the present technology comprising the local anestheticbupivacaine were prepared as described in Example 1, except the depotsof the present example comprised three of the depots of Example 1stacked on top of one another and heat compressed to form a new, thickersample having an overall film thickness of about 3 mm (for example, seethe configuration shown in FIG. 7).

In Vitro Drug Release Testing of Bupivacaine Depot.

in vitro drug release testing of the depots was performed as describedin Example 1.

Release Profiles.

FIG. 22 shows the average cumulative dose profiles of the bupivacainefilms. The graph shows controlled release of over 500 hours with theinitial 24-hour release of about 20%.

Example 3

Preparation of Bioresorbable Polymer/Drug Films.

Four depots of the present technology comprising the local anestheticbupivacaine were prepared as described below.

Each of the sample depots consisted of a heat compressed, multi-layerfilm formed of an inner depot similar to that shown in FIG. 5encapsulated by a different control region (described below). The innerdepot of each sample depot consisted of a therapeutic region (formed of10 heat-compressed therapeutic layers) sandwiched between two innercontrol layers (closest to the therapeutic region, such as 302 b and 302c in FIG. 5, and referred to as Control Layer A in Table 5 below) andtwo outer control layers (farthest from therapeutic region, such as 302a and 302 d in FIG. 5), and referred to as Control Layer B in Table 5).The constituents of the therapeutic region and the control region aredetailed in Table 5.

TABLE 5 10 heat-compressed microlayers Therapeutic Region PolymerPoly(L-lactide-co-ε-caprolactone)(PLCL) (Corbion; Lenexa, KS) having aPLA to PCL ratio of from 90:10 to 60:40 (880 mg) Releasing Agent Tween20 (440 mg) (Sigma-Aldrich Pte Ltd; Singapore) Anesthetic bupivacainehydrochloride (1760 mg) (Xi'an Victory Biochemical Technology Co., Ltd.;Shaanxi, People's Republic of China) DCM 13.33 g Anesthetic:Polymer 2:1Control Region Control Layer A Polymer PLCL (352 mg) Releasing AgentTween 20 (172 mg) DCM 5.3 g Control Layer B Polymer PLCL (352 mg)Releasing Agent Tween 20 (35 mg) DCM 5.3 g

Therapeutic Region.

The therapeutic region constituents (see Table 5 above) were added to aglass vial and mixed thoroughly. The resulting blend was poured onto aflat plate and drawn by a film applicator to form a thin film upondrying (<200 μm thickness).

Control Region.

The control region constituents (see Table 5 above) were added to aglass vial and mixed thoroughly. The resulting blend was poured onto aflat plate and drawn by a film applicator to form a thin film upondrying (<200 μm thickness).

For each sample film, 10 drug layers (each initially <200 μm thickness)and 4 control layers were aligned (Control B-Control A-10 therapeuticlayers-Control A-Control B) and compressed by a heat compressor (KunShan Rebig Hydraulic Equipment Co. Ltd.; People's Republic of China).The resulting thin film was cut to form a 20 mm×20 mm triangle samplewith an overall film thickness of <0.2 mm. The triangle samples werefurther aligned, and fully encapsulated, with (a) a Control Layer A onboth sides (i.e., two additional control layers), (b) a Control Layer Bon both sides (i.e., two additional control layers), (c) two of ControlLayer A on both sides (i.e., four additional control layers), (d) two ofControl Layer B on both sides (i.e., four additional control layers).The resulting assembly was then compressed by a heat compressor (KunShan Rebig Hydraulic Equipment Co. Ltd.; People's Republic of China).

In Vitro Drug Release Testing of Bupivacaine Depot.

The purpose of this procedure was to measure the release of bupivacaine,from a bioresorbable polymer depot into a receiving fluid of 1×PBS. Eachrelease experiment was conducted in duplicate. The in vitro releaseprocedure consisted of placing a known size of film into an apparatuscontaining the receiving fluid. The in vitro release apparatus consistedof either a 20 mL or a 100 mL glass bottle. A receiving fluid in theamount of 12 mL or 50 mL was added to each sample bottle. During therelease study, the apparatus was placed in a water bath maintained at37±2° C. At predetermined intervals, samples of the receiving fluid wereremoved and analyzed for bupivacaine concentration by a UV-VisibleSpectrophotometer.

Release Profiles.

FIG. 23 shows the average cumulative dose profiles of the bupivacainefilms. The graph shows controlled release of over 1500 hours for some ofthe configurations.

Example 4

Sample depots of the present technology were implanted subcutaneously inliving rabbits (one depot per rabbit). The depots were placed in asubcutaneous pocket.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5).

The present example tested two groups of depots, each utilizing adifferent polymer. The depots in Group A included Poly(DL-lactide-glycolide-ε-caprolactone) in a molar ratio of 60:30:10, andthe depots in Group B included Poly (DL-lactide-co-glycolide) in a molarratio of 50:50. Each group included a depot having a low, medium, orhigh dose of bupivacaine HCl.

For the depots of Group A, each inner control layer consisted of 3.9 mg,4.0 mg, or 4.7 mg of the polymer (for Low, Med, and High dose groups,respectively) and 1.9 mg, 2.0 mg, or 2.3 mg of a releasing agent(polysorbate 20) (for Low, Med, and High dose groups, respectively).Each outer control layer consisted of 5.3 mg, 5.5 mg, or 6.3 mg of thepolymer (for Low, Med, and High dose groups, respectively) and 1.9 mg,2.0 mg, or 2.3 mg of a releasing agent (polysorbate 20) (for Low, Med,and High dose groups, respectively).

For the depots of Group A, the therapeutic region consisted of 71.5 mg,152.6 mg, or 269 mg of the polymer (for Low, Med, and High dose groups,respectively), 34.9 mg, 74.6 mg, or 131.5 mg of a releasing agent(polysorbate 20) (for Low, Med, and High dose groups, respectively), and142.9 mg, 305.2 mg, or 538.1 mg of a local anesthetic (bupivacaine HCl).

For the depots of Group B, each inner control layer consisted of 4.7 mg,5.1 mg, or 5.3 mg of the polymer (for Low, Med, and High dose groups,respectively) and 2.3 mg, 2.5 mg, or 2.6 mg of a releasing agent(polysorbate 20) (for Low, Med, and High dose groups, respectively).Each outer control layer consisted of 6.4 mg, 6.9 mg, or 7.3 mg of thepolymer (for Low, Med, and High dose groups, respectively), and 0.6 mg,0.7 mg, or 0.7 mg of a releasing agent (polysorbate 20) (for Low, Med,and High dose groups, respectively).

For the depots of Group B, the therapeutic region consisted of 87.0 mg,171.1 mg, or 317.7 mg of the polymer (for Low, Med, and High dosegroups, respectively), 42.5 mg, 83.6 mg, or 155.2 mg of a releasingagent (polysorbate 20) (for Low, Med, and High dose groups,respectively), and 173.9 mg, 342.2 mg, or 635.4 mg of a local anesthetic(bupivacaine HCl).

Within each of Group A and Group B, the low dose depots were about 20mm×20 mm x<1 mm (e.g., 0.89 mm and 0.9 mm), the medium dose depots wereabout 20 mm×20 mm x<2 mm (e.g., 1.8 mm and 1.6 mm), and the high dosedepots were about 20 mm×20 mm x<3 mm (e.g., about 2.7 mm and about 2.8mm).

Blood draws for bupivacaine concentration analysis were collectedthrough Day 28.

Group A

The Group A depots were administered to 3 rabbits/dose group and PKsamples were collected to day 28. The semi-log plot of the group meandata for each dose is shown in FIG. 24A. The product, regardless ofdose, exhibits peak exposure within the first 72 hours and then aplateau of exposure that is determined by the dose (the higher the dosethe longer the plateau) followed by more rapid terminal clearance. Therelease of bupivacaine is rapid with a consistent similar profile foreach rabbit with moderate variability over the first 72 hours.

The in vitro pharmacokinetic (“PK”) profile for Group A is shown in FIG.24B. The half-life of the initial distribution phase through the first72-96 hours was generally consistent through the three dose strengths(implant sizes) and T_(max) occurred within the first 24 hours for allrabbits, with a median T_(max) between 4-8 hours. The peak exposure(C_(max)) for the high dose exhibited a low CV % of 17.6%. This datawould indicate a controlled initial rapid release of bupivacaine duringthe period of greatest discomfort post TKA surgery. The exposure profilewas stable from 72 hours through at least 436 hours. The terminal phasehalf-life started to exhibit the more innate half-life of bupivacaine,particularly in the high dose where the terminal phase t_(1/2) was 17.4hours. This would suggest that the depot had almost completely releasedthe drug by Day 21.

The high dose, Group A depot was consistent in average exposure from Day3 to Day 18, while the mid and low dose depots were consistent from Day3 to Day 14. There was not a significant difference in exposure betweenthe Mid and High dose groups from Day 3-14, while the Low dose wasapproximately half the exposure level during this time period.

Group B

Formulation 50:50 copolymer was administered to 3 rabbits/dose group andPK samples were collected to hour 672 (Day 28). The semi-log plot of thegroup mean data for each dose is presented in FIG. 24C. The product,regardless of dose, exhibits peak exposure within the first 72 hours andthen a gradual decline in exposure followed by a secondary fasterrelease coupled with a secondary peak in exposure at approximately Day19-21. After the secondary peak, bupivacaine exposure declined withdifferent rates dependent on dose (lower the dose the faster theclearance). FIG. 24C highlights the group mean (SD) and individualrabbits for Low Dose (126 mg) in Panel A, Mid Dose (252 mg) in Panel Band High Dose (420 mg) in Panel C through the first 96 hours. Therelease of bupivacaine is rapid with a consistent and similar profilefor each rabbit with moderate variability over the first 72 hours.

The in vitro pharmacokinetic profile is shown in FIG. 24D. The 50:50copolymer did not exhibit an initial distribution half-life like the 631terpolymer, however T_(max) occurred within the first 24 h for allrabbits, with a median T_(max) that was slightly further out in time,between 16-20 hours. The peak exposure (C_(max)) exhibited a very low CV% of 5.99%. This data would indicate a controlled initial rapid releaseof bupivacaine during the acute postoperative pain period (i.e., periodof greatest discomfort post TKA surgery) followed by a more gradualdecline in release rate through the subacute postoperative pain period,which is consistent with the presumed steady decline in pain during thatsame period. This release profile having the steady decline in releaserate during the acute postoperative pain period is in contrast with therelease rate of the 631 polymer formulation, where the release ratestates substantially constant throughout the postoperative pain period.

All three dose levels slowly decreased exposure over the Day 3 to Day 18time period.

Example 5

Two sample depots of the present technology were implanted in theintraarticular space of a knee joint of a living canine. The surgeonperformed a medial and lateral parapatellar arthrotomy to insert onesample depot in the medial gutter and one sample depot in the lateralgutter. The depots were anchored in place by 4-0 PDS II suture. Twocanines were the subject of the present study.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5). Each inner control layer consistedof 5.7 mg of a bioresorbable polymer (60:30:10 terpolymer Poly(DL-lactide-glycolide-ε-caprolactone)) and 2.8 mg of a releasing agent(polysorbate 20). Each outer control layer consisted of 7.7 mg of abioresorbable polymer (60:30:10 terpolymer Poly(DL-lactide-glycolide-ε-caprolactone)) and 0.8 mg of a releasing agent(polysorbate 20).

The therapeutic region comprised a single layer consisting of 118 mg ofa bioresorbable polymer (60:30:10 terpolymer Poly(DL-lactide-glycolide-ε-caprolactone)), 57.6 mg of a releasing agent(polysorbate 20), and 235.9 mg of a local anesthetic (bupivacaine HCl).

Each of the depots was about 15 mm×about 25 mm×about 1 mm.

Following implantation, the canines were evaluated at predeterminedintervals to determine the post-operative pharmacokinetic (PK) profileof bupivacaine in synovial fluid and blood plasma. For PK values ofbupivacaine in the blood plasma (i.e., representing systemic bupivacainelevels), blood was drawn at scheduled intervals after implantation ofthe depots. The PK results for the plasma fluid samples are shown atFIG. 25.

As shown in FIG. 25, the depot 100 released an initial, controlled burstover about the first three days, followed by a tapering release for theremaining 11 days.

Example 6

Three sample depots of the present technology were implanted in theintraarticular space of a knee joint of a living sheep. The surgeonperformed a medial and lateral parapatellar arthrotomy to insert onesample depot in the medial gutter and two sample depots in the lateralgutter. The lateral gutter depots were sutured side-by-side prior toimplantation to keep the depots in place relative to each other in thegutter. The depots were then anchored in place to the capsular tissue by4-0 PDS II suture.

Each of the sample depots consisted of a heat compressed, multi-layerfilm having the configuration shown in FIG. 5. The therapeutic regionconsisted of a single layer and was sandwiched between two inner controllayers (closest to the therapeutic layer, such as 302 b and 302 c inFIG. 5) and two outer control layers (farthest from therapeutic region,such as 302 a and 302 d in FIG. 5). Each inner control layer consistedof 5.3 mg of a bioresorbable polymer (Poly (DL-lactide-co-glycolide) ina molar ratio of 50:50)) and 2.6 mg of a releasing agent (polysorbate20). Each outer control layer consisted of 7.2 mg of a bioresorbablepolymer (Poly (DL-lactide-co-glycolide) in a molar ratio of 50:50)) and0.7 mg of a releasing agent (polysorbate 20).

The therapeutic region comprised a single layer consisting of 118.1 mgof a bioresorbable polymer (Poly (DL-lactide-co-glycolide) in a molarratio of 50:50), 57.7 mg of a releasing agent (polysorbate 20), and236.3 mg of a local anesthetic (bupivacaine HCl).

Each of the depots was about 15 mm×about 25 mm×about 1 mm.

Following implantation, the sheep was evaluated at 1, 4, 8, 15, and 30days to determine the post-operative pharmacokinetic (PK) profile ofbupivacaine in synovial fluid and blood plasma.

For PK values of bupivacaine in the blood plasma (i.e., representingsystemic bupivacaine levels), 1 mL of blood was drawn 1, 2, 4, 8, 12,16, 20, 24 and 48 hours after implantation of the depots, then every 48hours (at the same time as was drawn on previous days, +/−1 hr) in allanimals until day 28 prior to sacrifice. The PK results for the plasmafluid samples are shown in FIG. 26A. As shown, the systemic plasmabupivacaine concentration showed an initial, controlled burst over thefirst 2-4 days, followed by a tapering release for the remaining period.

For PK values of bupivacaine in the synovial fluid (i.e., representinglocal bupivacaine levels), a minimum of 0.5 mL of synovial fluid wasaspirated from the joint at 0 hours (i.e., just prior to surgery), 24hours, 96 hours, and 192 hours. The PK results for the synovial fluidsamples are shown in FIG. 26B. As shown, the local synovialconcentration showed an initial, controlled burst over the first 2-4days, followed by a tapering release for the remaining period.

FIG. 26C is a plot depicting the blood plasma bupivacaine concentrationversus the synovial bupivacaine concentration over time. As demonstratedin FIG. 26C, the PK values are illustrative of a release profileachieved in prior in vitro and in vivo studies, wherein the initial,controlled burst over the first 2-4 days provides a substantial dosageof bupivacaine during the acute postoperative pain period and thetapering release that follows provides a therapeutic dosage during thesubacute postoperative pain period. As shown, local bupivacaine levelswere an order of magnitude greater than systemic bupivacaine levels.Achieving a high local concentration of bupivacaine withoutcorrespondingly high systemic levels allows for optimized analgesiawithout the risk of systemic toxicity.

IV. SELECTED SYSTEMS AND METHODS FOR TREATING POSTOPERATIVE PAINASSOCIATED WITH ORTHOPEDIC SURGERY

The depots 100 of the present technology may be used to treat a varietyof orthopedic injuries or diseases depending upon the nature of thetherapeutic agent delivered as described above. The therapeutic agentmay be delivered to specific areas of the patient's body depending uponthe medical condition being treated. The depots 100 of the presenttechnology may be positioned in vivo proximate to the target tissue(i.e., bone, soft tissue, etc.) in the patient's body to provide acontrolled, sustained release of a therapeutic agent for the treatmentof a particular condition. This implantation may be associated with asurgery or intervention for acutely treating the particular condition,whereby the depot enables chronic, sustained pharmacological treatmentfollowing completion of the surgery or intervention. The depot may be astandalone element, or may be coupled to or integrated as part of animplantable device or prosthesis associated with the intervention orsurgery.

The amount of the therapeutic agent that will be effective in a patientin need thereof will depend on the specific nature of the condition, andcan be determined by standard clinical techniques known in the art. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The specific dose level for anyparticular individual will depend upon a variety of factors includingthe activity of the drug, the age, body weight, general physical andmental health, genetic factors, environmental influences, sex, diet,time of administration, location of administration, rate of excretion,and the severity of the particular problem being treated.

Some aspects of the present technology include a system comprising aplurality of depots (each of which could be any of the depots describedherein) provided for implantation by a clinical practitioner. In thissystem, each depot may be configured for controlled release oftherapeutic agent to tissue proximate to the implantation site of thedepot. The depots in the system may be identical or may vary in severalrespects (e.g., form factor, therapeutic agent, release profile, etc.).For example, the system may be comprised of a depot having a releaseprofile that provides for an immediate release of therapeutic agent andother depots comprised of a depot having a release profile that providesfor a delayed release of therapeutic agent.

Many depots of the present technology are configured to be implanted ata surgical site to treat postoperative pain at or near the site. As usedherein, the term “pain” includes nociception and the sensation of pain,both of which can be assessed objectively and subjectively, using painscores and other methods well-known in the art, such as opioid usage. Invarious embodiments, pain may include allodynia (e.g., increasedresponse to a normally non-noxious stimulus) or hyperalgesia (e.g.,increased response to a normally noxious or unpleasant stimulus), whichcan in turn be thermal or mechanical (tactile) in nature. In someembodiments, pain is characterized by thermal sensitivity, mechanicalsensitivity and/or resting pain. In other embodiments, pain comprisesmechanically-induced pain or resting pain. In still other embodiments,the pain comprises resting pain. The pain can be primary or secondarypain, as is well-known in the art. Exemplary types of pain reducible,preventable or treatable by the methods and compositions disclosedherein include, without limitation, include post-operative pain, forexample, from the back in the lumbar regions (lower back pain) orcervical region (neck pain), leg pain, radicular pain (experienced inthe lower back and leg from lumbar surgery in the neck and arm fromcervical surgery), or abdominal pain from abdominal surgery, andneuropathic pain of the arm, neck, back, lower back, leg, and relatedpain distributions resulting from disk or spine surgery. Neuropathicpain may include pain arising from surgery to the nerve root, dorsalroot ganglion, or peripheral nerve.

In various embodiments, the pain results from “post-surgical pain” or“post-operative pain” or “surgery-induced pain”, which are used hereininterchangeably, and refer to pain arising in the recovery period ofseconds, minutes, hours, days or weeks following a surgical procedure(e.g., hernia repair, orthopedic or spine surgery, etc.). Surgicalprocedures include any procedure that penetrates beneath the skin andcauses pain and/or inflammation to the patient. Surgical procedure alsoincludes arthroscopic surgery, an excision of a mass, spinal fusion,thoracic, cervical, or lumbar surgery, pelvic surgery or a combinationthereof.

FIGS. 27A and 27B illustrate common locations within a patient that maybe sites where surgery is conducted and locations where the depots ofthe present technology can be administered. It will be recognized thatthe locations illustrated in FIGS. 27A and 27B are merely exemplary ofthe many different locations within a patient where a surgery may takeplace. For example, surgery may be required at a patient's knees, hips,upper extremities, lower extremities, neck, spine, shoulders, abdomenand pelvic region. FIG. 28 is a table showing common surgical proceduresfor which the depots 100 of the present technology may be utilized fortreating postoperative pain.

Many embodiments of the present technology include one or more depots,having the same or different configuration and/or dosing, that areconfigured to be positioned at or near a surgical site of a knee jointto treat pain associated with a total knee replacement surgery. Aspreviously described, the depots of the present technology may be solid,self-supporting, flexible thin films that is structurally capable ofbeing handled by a clinician during the normal course of a surgerywithout breaking into multiple pieces and/or losing its general shape.This way, the clinician may position one or more of the depots atvarious locations at or near the intracapsular and/or extracapsularspace of the knee joint, as necessary to address a particular patient'sneeds and/or to target particular nerves innervating the knee.

FIGS. 29A-29C, for example, are front, lateral, and medial views of ahuman knee, showing the location of the nerves innervating the extra-and intracapsular portion of a knee joint. In some embodiments, thedepots may be implanted adjacent to one or more nerves (such as thenerves shown in FIGS. 29A-29C) innervating the knee.

In some instances, it may be beneficial to position one or more of thedepots within the joint capsule. For example, FIG. 30A is a splayed viewof a human knee exposing the intracapsular space and identifyingpotential locations for positioning one or more depots, and FIG. 30B isa splayed view of a human knee exposing the intracapsular space andshowing several depots 100 positioned within for treating postoperativepain. As shown in FIGS. 30A and 30B, in some instances, one or moredepots may be positioned at or near the suprapatellar pouch SPP,specifically under the periosteum and attached to the quadriceps tendon.Additional areas for placement of one or more depots 100 may includegenerally the medial and lateral gutters MG, LG (including optionalfixation to tissue at the medial or lateral side of the respectivegutter), on the femur F, on the tibia T (e.g., posterior attachment tothe tibial plateau, at or near the anterior tibia to anesthetizeinfrapatellar branches of the saphenous nerve). In some embodiments, oneor more depots may be positioned adjacent to at least one of a posteriorcapsule PC of the knee, a superior region of the patella P, and/or thearthrotomy incision into the knee capsule. In some embodiments, one ormore depots 100 may be positioned at or near the saphenous nerve, theadductor canal, and/or the femoral nerve. In some embodiments, one ormore of the depots may be configured to be positioned at or near aninfrapatellar branch of the saphenous nerve, one or more genicularnerves of the knee, a superior region of the patella P. It may bedesirable to position the depot within the knee capsule but away fromany articulating portions of the knee joint itself.

Instead of or in addition to the placement of depots within theintracapsular space, one or more depots may be placed at anextracapsular position. FIGS. 31A and 31B, for example, show anteriorand posterior views, respectively, of the nerves as positioned at anextracapsular location. In some embodiments, the depots may be implantedadjacent to one or more extracapsular nerves (such as the nerves shownin FIGS. 31A and 31B). As shown in FIG. 32, in some embodiments one ormore depots 100 may be positioned along or adjacent the subcutaneousskin incision.

In some embodiments, the system includes a first depot (or plurality ofdepots) and a second depot (or plurality of depots), all of which areconfigured to be implanted at or near the knee joint. The first depot(s)may have the same or different release profile, rate of release,therapeutic agent (such as non-anesthetic analgesics, NSAIDs,antibiotics, etc.), duration of release, size, shape, configuration,total payload, etc. as the second depot(s).

So as not to interfere or overlap with a peripheral nerve blockadministered perioperatively to the patient, one or more of the depotsmay optionally include a delay release capability for 6 to 24 hoursfollowing implantation. In some embodiments, one or more depots placedin the adductor canal and knee capsule may be configured to have a delayin the release of therapeutic agent that may exceed 24 hours.

The depots 100 disclosed herein may be used to treat postoperative painassociated with other knee surgeries. For example, one or more depotsmay be used to treat postoperative pain associated with an ACL repairsurgery, a medial collateral ligament (“MCL”) surgery, and/or aposterior cruciate ligament (“PCL”) surgery. For ACL repair, one or moredepots may be positioned to delivery analgesic the femoral and/orsciatic nerves, while for PCL repair surgery, one or more depots may bepositioned parasacral to deliver analgesic to the sciatic nerve. The oneor more depots may be used to treat postoperative pain associated with apartial knee replacement surgery, total knee replacement surgery, and/ora revision surgery of a knee replacement surgery. In such procedures,one or more depots can be placed contiguous to the joint or repair siteto provide a local block, or else may suitably positioned to provide aregional block by delivering an analgesic to one or more of the femoralnerve or the sciatic nerve, for example via placement in the adductorcanal.

In addition to the knee-related surgeries described above, embodimentsof the depots disclosed herein can be used to treat postoperative painassociated with other orthopedic surgeries as described in more detailbelow and as summarized in part in FIG. 28. Examples include surgicalprocedures involving the ankle, hip, shoulder, wrist, hand, spine, legs,or arms. For at least some of these surgical procedures, analgesic canbe provided to deliver a local block or a regional block to treatpostoperative pain. For a local block, one or more depots can beattached under direct vision in open surgery, for example during jointarthroplasty, open reduction and internal fixation (ORIF) surgery,ligament reconstruction, etc. In such procedures involving a joint, oneor more depots can be positioned at the joint capsule (e.g., at or nearthe intracapsular and/or extracapsular space of the joint) or adjacentsoft tissues spaced apart from articulating surfaces to avoid the depotinterfering with joint movement or being damaged by contact witharticulating surfaces. In cases involving fracture repair or ligamentrepair, one or more depots can be positioned at or adjacent to therepair site to provide a local block. For a regional block, one or moredepots can be deposited at a treatment site adjacent to the target nervevia ultrasound guidance using a blunt trocar catheter or other suitableinstrument. In at least some embodiments, it can be beneficial tocombine delivery of analgesic or other therapeutic agents via thedepot(s) with delivery of NSAIDs, a long-acting narcotic deliveredpre-operatively, and/or acetaminophen. The sustained, controlled,release of an analgesic via the one or more depots may work in concertwith these other therapeutic agents to provide a reduction inpostoperative pain associated with orthopedic and other surgicalprocedures.

In one example, one or more depots as described herein can be used totreat postoperative pain associated with foot and ankle surgeries suchas ankle arthroplasty (including ankle revision, ankle replacement, andtotal ankle replacement), ankle fusion, ligament reconstruction,corrective osteotomies (e.g., bunionectomy, pes planus surgery), or openreduction and internal fixation (ORIF) of ankle or foot fractures. Intreating postoperative pain associated with such surgeries, one or moredepots can be configured and positioned adjacent to the joint or repairsite to provide a local block. Additionally or alternatively, one ormore depots can be placed parasacral or at another suitable location totarget one or more of the subgluteal sciatic nerve, popliteal sciaticnerve, deep peroneal nerve, or the superficial peroneal nerve. In someembodiments, depots positioned to treat postoperative pain associatedwith ankle or foot surgeries can have a release profile configured todeliver therapeutically beneficial levels of analgesic for a period ofbetween 3-7 days.

In another example, one or more depots as described herein can be usedto treat postoperative pain associated with hip surgeries such as hiparthroplasty (including hip revision, partial hip replacement, and totalhip replacement) or open reduction and internal fixation (ORIF) of hipfactures. In treating postoperative pain associated with such surgeries,one or more depots can be configured and positioned adjacent to thejoint or repair site to provide a local block. Additionally oralternatively, a regional block can be provided by placing depots in thepsoas compartment, lumbar paravertebral space, fascia iliaca, or othersuitable location to target one or more of the lumbar plexus, sacralplexus, femoral nerve, sciatic nerve, superior gluteal nerve, orobturator nerve. In some embodiments, it may be beneficial to secure theone or more depot(s) (e.g., using a fixation mechanism as describedherein) to maintain an anterior position of the depot, therebypreventing or reducing exposure of analgesic to motor nerves (e.g.,sciatic or femoral nerves). In some embodiments, depots positioned totreat postoperative pain associated with hip surgeries can have arelease profile configured to deliver therapeutically beneficial levelsof analgesic for a period of 5-7 or 7-10 days depending on theparticular surgical procedure.

Post-operative pain associated with shoulder and upper-arm surgeries canlikewise be treated using one or more depots as disclosed herein.Examples of such surgeries include shoulder arthroplasty (includingshoulder revision, partial shoulder replacement, and total shoulderreplacement), upper-arm fracture repair (scapular, humerus),ligament/tendon repair (e.g., rotator cuff, labrum, biceps, etc.), oropen reduction and internal fixation (ORIF) of fractures of the shoulderor upper arm. In treating postoperative pain associated with suchsurgeries, one or more depots can be configured and positioned adjacentto the joint or repair site to provide a local block. Additionally oralternatively, one or more depots can be configured and positioned totarget the brachial plexus by placing one or more depots in the cervicalparavertebral space, interscalene, or supraclavicular space. In someembodiments, interscalene placement of the depots can avoid exposure ofanalgesic to native cartilage, thereby reducing the risk ofchondrotoxicity. In some embodiments, depots positioned to treatpostoperative pain associated with shoulder or upper-arm relatedsurgeries can have a release profile configured to delivertherapeutically beneficial levels of analgesic for a period of 3-7 days.

In another example, one or more depots as described herein can be usedto treat postoperative pain associated with elbow surgeries such aselbow arthroplasty (including elbow revision, partial elbow replacement,and total elbow replacement), ligament reconstruction, or open reductionand internal fixation (ORIF) of fractures of the elbow. In treatingpostoperative pain associated with such surgeries, one or more depotscan be positioned adjacent to the joint or repair site to provide alocal block. Additionally or alternatively, one or more depots can beconfigured and positioned to target the brachial plexus nerves, forexample by being placed at or near the cervical paravertebral space,infraclavicular, or axillary position, or other suitable location. Insome embodiments, depots positioned to treat postoperative painassociated with elbow surgeries can have a release profile configured todeliver therapeutically beneficial levels of analgesic for a period of3-7 days.

Post-operative pain associated with wrist and hand surgeries can also betreated using one or more depots as described herein. Examples of wristand hand surgeries include wrist arthroplasty (including wrist revision,partial wrist replacement, and total wrist replacement), wrist fusion,and open reduction and internal fixation (ORIF) of fractures of thewrist. In treating postoperative pain associated with such surgeries,one or more depots can be configured and positioned adjacent to thewrist joint or repair site to provide a local block. Additionally oralternatively, one or more depots can be configured and positioned totarget the target the ulnar, median, radial, and cutaneous forearmnerves, for example via placement at the antecubital fossa, cervicalparavertebral space, infraclavicular, or axillary position. In someembodiments, depots positioned to treat postoperative pain associatedwith wrist and hand surgeries can have a release profile configured todeliver therapeutically beneficial levels of analgesic for a period of3-7 days.

The depots disclosed herein may likewise be used to treat postoperativepain from other orthopedic surgeries. For example, post-operative painassociated with spinal fusion can be treated via placement of one ormore depots subcutaneously or in the paravertebral space. In treatmentof post-operative pain associated with fibular fracture repair, one ormore depots can be configured and placed to target the sciatic nerveand/or the popliteal sciatic nerve, for example being placed parasacral.Various other placements and configurations are possible to providetherapeutic relief from post-operative pain associated with orthopedicsurgical procedures.

V. SELECTED SYSTEMS AND METHODS FOR TREATING POSTOPERATIVE PAINASSOCIATED WITH NON-ORTHOPEDIC SURGERY

The depots 100 of the present technology may be used to treat a varietyof medical conditions depending upon the nature of the therapeutic agentdelivered as described above. The therapeutic agent may be delivered tospecific areas of the patient's body depending upon the medicalcondition being treated. The depots 100 of the present technology may bepositioned in vivo proximate to the target tissue in the patient's bodyto provide a controlled, sustained release of a therapeutic agent forthe treatment of a particular condition. This implantation may beassociated with a surgery or intervention for acutely treating theparticular condition, whereby the depot enables chronic, sustainedpharmacological treatment following completion of the surgery orintervention. The depot 100 may be a standalone element, or may becoupled to or integrated as part of an implantable device or prosthesisassociated with the intervention or surgery.

The amount of the therapeutic agent that will be effective in a patientin need thereof will depend on the specific nature of the condition, andcan be determined by standard clinical techniques known in the art. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The specific dose level for anyparticular individual will depend upon a variety of factors includingthe activity of the drug, the age, body weight, general physical andmental health, genetic factors, environmental influences, sex, diet,time of administration, location of administration, rate of excretion,and the severity of the particular problem being treated.

Some aspects of the present technology include a system comprising aplurality of depots (each of which could be any of the depots describedherein) provided for implantation by a clinical practitioner. In thissystem, each depot may be configured for controlled release oftherapeutic agent to tissue proximate to the implantation site of thedepot. The depots in the system may be identical or may vary in severalrespects (e.g., form factor, therapeutic agent, release profile, etc.).For example, the system may be comprised of a depot having a releaseprofile that provides for an immediate release of therapeutic agent andother depots comprised of a depot having a release profile that providesfor a delayed release of therapeutic agent.

Many depots of the present technology are configured to be implanted ata surgical site to treat postoperative pain at or near the site. As usedherein, the term “pain” includes nociception and the sensation of pain,both of which can be assessed objectively and subjectively, using painscores and other methods well-known in the art, such as opioid usage. Invarious embodiments, pain may include allodynia (e.g., increasedresponse to a normally non-noxious stimulus) or hyperalgesia (e.g.,increased response to a normally noxious or unpleasant stimulus), whichcan in turn be thermal or mechanical (tactile) in nature. In someembodiments, pain is characterized by thermal sensitivity, mechanicalsensitivity and/or resting pain. In other embodiments, pain comprisesmechanically-induced pain or resting pain. In still other embodiments,the pain comprises resting pain. The pain can be primary or secondarypain, as is well-known in the art. Exemplary types of pain reducible,preventable or treatable by the methods and compositions disclosedherein include, without limitation, include post-operative pain andneuropathic pain of the arm, neck, back, lower back, leg, and relatedpain distributions. Neuropathic pain may include pain arising fromsurgery to the nerve root, dorsal root ganglion, or peripheral nerve.

In various embodiments, the pain results from “post-surgical pain” or“post-operative pain” or “surgery-induced pain,” which are used hereininterchangeably, and refer to pain arising in the recovery period ofseconds, minutes, hours, days or weeks following a surgical procedure.Surgical procedures include any procedure that penetrates beneath theskin and causes pain and/or inflammation to the patient. Surgicalprocedure also includes arthroscopic surgery, an excision of a mass,spinal fusion, thoracic, cervical, or lumbar surgery, pelvic surgery,chest-related surgery, breast-related surgery, gynecological orobstetric surgery, general, abdominal, or urological surgery, ear, nose,and throat (ENT) surgery, oral and maxillofacial surgery, oncologicalsurgery, cosmetic surgery, or a combination thereof. FIG. 28 is a tableshowing common surgical procedures for which the depots 100 of thepresent technology may be utilized for treating postoperative pain.

Many embodiments of the present technology include one or more depots,having the same or different configuration and/or dosing, that areconfigured to be positioned at or near a surgical site to treat painassociated with recovering from a surgical procedure. As previouslydescribed, the depots of the present technology may be solid,self-supporting, flexible thin films that is structurally capable ofbeing handled by a clinician during the normal course of a surgerywithout breaking into multiple pieces and/or losing its general shape.This way, the clinician may position one or more of the depots atvarious locations at or near the treatment site, as necessary to addressa particular patient's needs and/or to target particular nervesinnervating the surgical site.

In some embodiments, the system includes a first depot (or plurality ofdepots) and a second depot (or plurality of depots), all of which areconfigured to be implanted at or near the treatment site. The firstdepot(s) may have the same or different release profile, rate ofrelease, therapeutic agent contained (such as non-anesthetic analgesics,NSAIDs, antibiotics, etc.), duration of release, size, shape,configuration, total payload, etc. as the second depot(s).

So as not to interfere or overlap with a peripheral nerve blockadministered perioperatively to the patient, one or more of the depotsmay optionally include a delay release capability for 6 to 24 hoursfollowing implantation. In some embodiments, one or more depots placedat the treatment site may be configured to have a delay in the releaseof therapeutic agent that may exceed 24 hours.

The depots disclosed herein may be used to treat postoperative painassociated with a wide variety of surgeries. For example, as summarizedin FIG. 28, the depots may be used to treat postoperative pain forchest-related surgery, breast-related surgery, gynecological orobstetric surgery, general, abdominal, or urological surgery, ear, nose,and throat (ENT) surgery, oral and maxillofacial surgery, oncologicalsurgery, or cosmetic surgery). For particular surgeries or classes ofsurgeries, one or more depots can be positioned at a treatment site totreat postoperative pain. The treatment site may be at or near thesurgical site, or in some embodiments may be separated from the surgicalsite and proximate to a target nerve or nerve bundle that innervates thesurgical site.

In one example, one or more depots as described herein can be used totreat postoperative pain associated with chest-related surgeries such asa thoracotomy, esophageal surgery, cardiac surgery, lung resection,thoracic surgery, or other such procedure. In treating postoperativepain associated with such surgeries, one or more depots can beconfigured and positioned to target the intercostal nerves, for exampleby being placed at or near the thoracic paravertebral space or othersuitable location. Analgesics delivered to the intercostal nerves canreduce pain in a patient's chest area, thereby relieving postoperativepain associated with the above-noted chest-related surgical procedures.

In another example, one or more depots disclosed herein can be used totreat postoperative pain associated with breast-related surgeries suchas a mastectomy, breast augmentation, breast reduction, breastreconstruction procedure, or other such procedure. To treatpostoperative pain from such procedures, one or more depots can bepositioned and configured to deliver analgesics or other therapeuticagents to the intercostal nerves, for example via placement at or nearthe patient's infraclavicular space or other suitable location.Additionally or alternatively, one or more depots can be positioned andconfigured to deliver analgesics or other therapeutic agents to thelateral pectoral nerve and/or the medial pectoral nerve, for example viaplacement between the serratus anterior muscle and the latissimus dorsimuscle or other suitable location. As noted above, analgesics deliveredto the intercostal nerves can reduce pain in a patient's chest area,while analgesics delivered to the lateral and/or medial pectoral nervescan reduce pain in the pectoralis major and pectoralis minor, therebyreducing postoperative pain associated with the above-notedchest-related surgical procedures.

As another example, one or more depots can be used to treatpostoperative pain associated with general, abdominal, and/or urologicalprocedures. Examples of such procedures include proctocolectomy,pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidneytransplant, nephrectomy, radical prostatectomy, nephrectomy,gastrectomy, small bowel resection, splenectomy, incisional herniarepair, inguinal hernia repair, sigmoidectomy, liver resection,enterostomy, rectum resection, kidney stone removal, and cystectomyprocedures. For such operations, postoperative pain can be treated byplacing one or more depots to target nerves at the transverse abdominisplane (TAP). Analgesics delivered to the TAP can anesthetize the nervesthat supply the anterior abdominal wall, thereby reducing postoperativepain in this region. In some embodiments, one or more depots aredisposed between the internal oblique and transverse abdominis muscles.In some embodiments, one or more depots can be disposed at or adjacentto the abdominal wall, for example being secured in place via fixationmechanisms as described in more detail below.

In some embodiments, one or more depots are used to treat postoperativepain associated with gynecological and obstetric surgeries, for examplea myomectomy, Caesarian section, hysterectomy, oophorectomy, pelvicfloor reconstruction, or other such surgical procedure. For suchprocedures, the depot(s) can be configured and positioned to deliveranalgesics or other therapeutic agents to one or more of the nervesinnervating the pelvic and/or genital area, for example the pudendalnerve, intercostal nerve, or other suitable nerve.

In some embodiments, one or more depots can be used to treatpostoperative pain associated with ear, nose, and threat (ENT) surgicalprocedures, for example tonsillectomy, submucosal resection,rhinoplasty, sinus surgery, inner ear surgery, parotidectomy,submandibular gland surgery, or other such operation. Similarly, one ormore depots can be used to treat postoperative pain associated with oraland maxillofacial surgeries, for example dentoalveolar surgery, dentalimplant surgery, orthognathic surgery, temporomandibular joint (TMJ)surgery, dental reconstruction surgeries, or other such operations. ForENT surgical procedures and oral and maxillofacial surgical procedures,the depot(s) can be configured and positioned to deliver analgesics orother therapeutic agents to one or more of the nerves innervatingregions affected by the surgical procedure, for example the mandibularnerve, the mylohyoid nerve, lingual nerve, inferior alveolar nerve,buccal nerve, auriculotemporal nerve, anterior ethmoidal nerve, or othersuitable nerve.

One or more depots 100 can also be used to treat postoperative pain forother surgical procedures, for example oncological surgeries (e.g.,tumor resection), cosmetic surgeries (e.g., liposuction), or othersurgical procedure resulting in postoperative pain. For treatment ofpostoperative pain associated with any particular surgery, the number ofdepots and the characteristics of individual depots can be selected todeliver the desired therapeutic benefits. For example, the dimensions ofthe depot(s), the amount of therapeutic agent per depot, the releaseprofile, and other characteristics can be tuned to provide the desiredtreatment of postoperative pain. For example, while a patient recoveringfrom a knee-replacement surgery may benefit from delivery of analgesicsfor at least 14 days, a patient recovering from a tonsillectomy may notrequire the same level or duration of analgesic drug delivery. As such,depots delivered to a patient for treatment of postoperative painfollowing a tonsillectomy may require fewer depots, or depots having asmaller payload of therapeutic agent, or depot(s) having a steeperrelease profile, etc. Additionally, the number and characteristics ofthe depot(s) selected for implantation can be tailored to accommodatethe target anatomical region for placement in the patient's body.

VI. CONCLUSION

Although many of the embodiments are described above with respect tosystems, devices, and methods for treating postoperative pain, thetechnology is applicable to other applications and/or other approaches.For example, the depots of the present technology may be used to treatpostoperative pain associated with a veterinary procedure and/orsurgery. Moreover, other embodiments in addition to those describedherein are within the scope of the technology. Additionally, severalother embodiments of the technology can have different configurations,components, or procedures than those described herein. A person ofordinary skill in the art, therefore, will accordingly understand thatthe technology can have other embodiments with additional elements, orthe technology can have other embodiments without several of thefeatures shown and described above with reference to FIGS. 2-32.

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Where the context permits, singular or plural terms mayalso include the plural or singular term, respectively. Althoughspecific embodiments of, and examples for, the technology are describedabove for illustrative purposes, various equivalent modifications arepossible within the scope of the technology, as those skilled in therelevant art will recognize. For example, while steps are presented in agiven order, alternative embodiments may perform steps in a differentorder. The various embodiments described herein may also be combined toprovide further embodiments.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

Unless otherwise indicated, all numbers expressing quantities ofingredients, percentages or proportions of materials, reactionconditions, and other numerical values used in the specification andclaims, are to be understood as being modified in all instances by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon thedesired properties sought to be obtained by the present technology. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques. Additionally, all ranges disclosed herein are to beunderstood to encompass any and all subranges subsumed therein. Forexample, a range of “1 to 10” includes any and all subranges between(and including) the minimum value of 1 and the maximum value of 10,i.e., any and all subranges having a minimum value of equal to orgreater than 1 and a maximum value of equal to or less than 10, e.g.,5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. For example,reference to “a therapeutic agent” includes one, two, three or moretherapeutic agents.

The headings above are not meant to limit the disclosure in any way.Embodiments under any one heading may be used in conjunction withembodiments under any other heading.

1. A depot for the treatment of postoperative pain via sustained,controlled release of an analgesic, comprising: a therapeutic regioncomprising the analgesic; a control region comprising a bioresorbablepolymer and a releasing agent mixed with the polymer, wherein thereleasing agent is configured to dissolve when the depot is placed invivo to form diffusion openings in the control region; and wherein thedepot is configured to be implanted at a treatment site in vivo and,while implanted, release the analgesic at the treatment site for no lessthan 7 days.
 2. The depot of claim 1, wherein the analgesic in thetherapeutic region comprises at least 50% of the total weight of thedepot.
 3. The depot of claim 1, wherein the depot is configured torelease the analgesic at the treatment site for no less than 14 days. 4.The depot of claim 3, wherein about 20% to about 50% of the analgesic isreleased in the first about 3 to about 5 days of the 14 days, andwherein at least 80% of the remaining analgesic is released in the last11 days of the 14 days.
 5. The depot of claim 3, wherein about 20% toabout 40% of the analgesic is released in the first 3 days of the 14days, and wherein at least 80% of the remaining analgesic is released inthe last 11 days of the 14 days.
 6. The depot of claim 3, wherein atleast 90% of the remaining analgesic is released in the last 11 days ofthe 14 days.
 7. The depot claim 3, wherein no more than 15% of theamount of analgesic is released in the first 2 days of the 14 days. 8.The depot claim 1, wherein the depot is configured to release theanalgesic at a first rate for a first period of time and at a secondrate for a second period of time.
 9. The depot of claim 8, wherein thefirst rate is greater than the second rate.
 10. The depot of claim 9,wherein the depot is configured to release at least 90% of the analgesicin the therapeutic region within 14 days.
 11. The depot of claim 1,wherein the depot is configured to release about 100 mg to about 500 mgof analgesic to the treatment site per day.
 12. A depot for thetreatment of postoperative pain via sustained, controlled release of ananalgesic, comprising: a therapeutic region comprising the analgesic; acontrol region comprising a bioresorbable polymer and a releasing agentmixed with the polymer, wherein the releasing agent is configured todissolve when the depot is placed in vivo to form diffusion openings inthe control region; wherein the depot is configured to be implanted at atreatment site in vivo and, while implanted, release the analgesic atthe treatment site for no less than 14 days, and wherein about 20% toabout 40% of the analgesic is released in the first 3 days of the 14days, and wherein at least 80% of the remaining analgesic is released inthe last 11 days of the 14 days.
 13. A depot for the treatment ofpostoperative pain via sustained, controlled release of an analgesic,comprising: a therapeutic region comprising the analgesic; a controlregion comprising a bioresorbable polymer and a releasing agent mixedwith the polymer, wherein the releasing agent is configured to dissolvewhen the depot is placed in vivo to form diffusion openings in thecontrol region; wherein the depot is configured to be implanted at atreatment site in vivo and, while implanted, release the analgesic atthe treatment site for no less than 3 days, and wherein the controlregion does not include the analgesic at least prior to implantation ofthe depot at the treatment site. 14-21. (canceled)